Human inborn errors of immunity: 2024 Update on the classification from the International Union of

Immunological Societies Expert Committee

M. Cecilia Poli1,2, Ivona Aksentijevich3, Aziz Bousfiha4, Charlotte Cunningham-Rundles5, Sophie Hambleton6,
Christoph Klein7, Tomohiro Morio8, Capucine Picard9, Anne Puel10,11,12, Nima Rezaei13, Mikko R. J. Seppänen14,
Raz Somech15, Helen C. Su16, Kathleen E. Sullivan17, Troy R. Torgerson18, Isabelle Meyts19, Stuart G. Tangye20,21

1
Program of Immunogenetics and Translational Immunology, ICIM, Faculty of Medicine, Clínica Alemana-
Universidad del Desarrollo, Santiago, Chile
2
Hospital de Niños Dr. Roberto del Río, Santiago Chile
3
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
4
Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
5
Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY, USA
6
Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
7
Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany, EU
8
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
9
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, APHP, Paris, France and
Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute,
Necker Hospital for Sick Children, Université Paris Cité, Paris, France, EU
10
Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital, 75015 Paris, France,
EU
11
Université Paris Cité, Imagine Institute, 75015 Paris, France, EU.
12
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller
University, New York, NY, USA
13
Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences,
Tehran, Iran.
14
Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center and Rare Diseases Center,
Children's Hospital, University of Helsinki, and Helsinki University Hospital.
15
Pediatric Department and Immunology Unit, Sheba Medical Center, Tel Aviv, Israel.
16
Laboratory of Clinical Immunology & Microbiology, Division of Intramural Research, National Institute of
Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
17
Division of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, University of
Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
18
Allen Institute for Immunology, Seattle, Washington, USA.
19
Department of Immunology and Microbiology, Laboratory for Inborn Errors of Immunity, Department of
Pediatrics, University Hospitals Leuven, and KU Leuven, 3000 Leuven, Belgium, EU.
20
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
21
School of Clinical Medicine, Faculty of Medicine, UNSW Sydney, NSW, Australia

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Corresponding authors:
Isabelle Meyts [email protected]

Stuart Tangye [email protected]

Key words: inborn errors of immunity, immune dysregulation, primary immunodeficiencies, autoinflammatory
disorders, IUIS Committee update

Abstract
This report provides an updated classification of Inborn Errors of Immunity (IEI), encompassing a total of 555
IEIs, and 17 phenocopies due to mutations in 504 different genes. Of these, we report 63 novel monogenic gene
defects and 2 phenocopies due to autoantibodies or somatic mutations, which have either been discovered since
the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or
expanded. The new additions were made after rigorous review of new genetic descriptions of IEI by the
International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI.
Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.)
and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified
according to the most consistently reported phenotype. In addition, because different variants in a single gene can
result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical
manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This
report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular
diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to
also serve as a valuable resource for all disciplines of medicine, since patients with IEI may be first seen by
rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists,
depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and
related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms,
which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such
knowledge may not only contribute to improved patient diagnosis and management and pave the way to the
development and implementation of therapies that target the cause – rather than the symptoms – of these
conditions.

Main text
Introduction
Inborn errors of immunity (IEIs) are, by definition, caused by damaging germline variants in single genes. IEIs
present clinically as increased susceptibility to infections, autoimmunity, autoinflammation, allergy, bone marrow
failure, and/or malignancy. Although individual IEI are rare, IEIs as a group are not, and they represent a

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significant health burden 1. Indeed, a recent study reported that the incidence of IEIs in the USA was 6 per 10,000
people2. Genetic variants underlie IEI by altering the encoded gene product, such as abolition (null) or reduction
(hypomorphic) of protein expression, titration of the intrinsic function of the protein (gain- or loss-of-function,
GOF or LOF), or acquiring novel functions (neomorphic)3,4. Mechanisms of disease in IEIs depend on the nature
of the variant and the mode of inheritance. Thus, monoallelic variants can cause disease by haploinsufficiency,
negative dominance, or GOF. By contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause
autosomal recessive (AR) traits by loss of expression, loss-of-function (LOF), GOF or neomorphic function of
the encoded protein. X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in
hemizygosity in males, or homozygous state in females.
The careful genetic dissection and functional study of individual IEI has aided in confirming or
contrasting the knowledge obtained from mouse models or has offered novel insights on protein function within
different immune pathways and specific immune cells5,6. Thus, by linking defined monogenic defects with clinical
phenotypes of immune dysregulation, IEIs represent elegant models of the human immune system and have thus
been referred to as “experiments of nature.”7 IEIs have also revealed mechanisms of disease pathogenesis and
enabled the implementation of gene- or pathway-specific therapies for the treatment of rare and common
conditions and established fundamental aspects of human immunology8-10. Thus, the study of IEI has driven
profound advances in molecular medicine and human biology.
Since 1970, an international expert committee comprising pediatric and adult clinical immunologists,
clinician/scientists and researchers in basic immunology – initially under the auspices of the World Health
Organization and currently the International Union of Immunological Societies (IUIS) – has provided the clinical
and research communities with an update of genetic causes of immune deficiency and dysregulation
https://iuis.org/committees/iei/.
IEIs are currently categorized into 10 Tables, with sub-tables segregating groups of disorders into overlapping
phenotypes. These tables describe: Combined immunodeficiencies (Table I; 3 sub-tables); Combined
immunodeficiencies with syndromic features (Table II; 9 sub-tables); Predominantly antibody deficiencies (Table
III; 3 sub-tables); Diseases of immune dysregulation (Table IV; 7 sub-tables); Congenital defects of phagocytes
(Table V; 4 sub-tables); Defects in intrinsic and innate immunity (Table VI; 9 sub-tables); Autoinflammatory
diseases (Table VII; 3 sub-tables); Complement deficiencies (Table VIII); Bone Marrow Failure (Table IX), and
Phenocopies of inborn errors of immunity (Table X)(Figure 1 A, B)4.
The committee strives to publish an updated report every 2 years to consolidate advances and catalogue
current IEIs4. A large array of genetic variants related to IEI have been reported recently. Rather than including
every candidate gene published in the peer-reviewed scientific literature, the committee applies stringent criteria
to classify gene defects as novel causes of IEIs11. These criteria include:

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 1. The candidate genotype is monogenic and is not found in individuals without the clinical phenotype
(recognizing that some conditions have incomplete penetrance).
2. Experimental studies establish that the genetic variant impairs, destroys, or alters expression or function
of the gene product.
3. The causal relationship between the candidate genotype and the clinical phenotype must be confirmed
via a relevant cellular phenotype, including – where possible – rescue of a functional defect11.

These criteria can be met by the publication of multiple cases from unrelated families, including detailed
immunologic data; or publication of very few - even single - cases with compelling mechanistic data, often
revealed from complementary studies in animal or cell culture models. With the number of genes and conditions
growing, the committee also considers it essential that the immunological phenotype is described in-depth beyond
the clinical phenotype. We also considered whether sufficient justification was provided to exclude alternative
candidate gene variants identified in single cases, the depth of the clinical descriptions of the affected individuals,
and the level of immune and functional characterization. It is important to consider that for specific diseases, even
though at this point they fulfill the criteria to be included in these tables, building evidence may argue against
disease causality. Indeed, stringent criteria are being developed to remove certain genes or inheritance modes
from this list in the future.
This 2024 Update is intended as a follow-up resource for clinicians and researchers, and it can guide the
design of panels used for targeted gene sequencing to facilitate clinical genetic diagnoses of IEI. Here, we
summarize data on the genetic cause of 63 novel IEIs, and 2 phenocopies due to autoantibodies (n=1) or somatic
mutations (n=1), that have been assessed since the previous update12 increasing the number of monogenic IEI to
555 including 4 CNVs (Figure 1A) due to pathogenic variability in 504 different genes including KRAS, NRAS
and UBA1 for which disease is only described due to somatic variants. (Supplementary Table 1). Given the rapid
pace of discovery, the current update will likely be outdated by the time of its publication.

One gene, several phenotypes

For this update, IEIs are classified according to the predominant clinical presentation. However, patients with
pathogenic mutations in specific IEI-associated genes may have clinical presentations that differ from the
predominant clinical presentation under which they have been classified in this document, thereby expanding the
phenotypic spectrum of disease. In this regard, some previously reported genes and IEI have been reclassified
into a different table after panel discussion. Nevertheless, it is important to stress that a disease-causing effect of
a genetic variant cannot be excluded solely because the description of the classic phenotype in this table does not
fit with the clinical presentation of a given patient. Indeed, the presenting phenotype of many IEIs is gradually
expanding. One example of this are mutations in the WD domain of COPA causing COPA syndrome with arthritis

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and alveolar haemorrhages as the main clinical manifestations13. However, patients with mutations in the C-
terminal domain can have a wide spectrum of clinical manifestations including autoimmunity and
neuroinflammation14. It is therefore challenging to exclude pathogenicity of a novel variant, even if the phenotype
is not typical for the described gene defect as the mechanism of disease and phenotype may differ based on the
location of the variant.

Re-defining or broadening of the clinical phenotype can also occur simply by the description of additional
patients. Examples include AR MYD88 and IRAK4 deficiencies, which have been associated with susceptibility
to invasive pyogenic bacterial infections, but recently have been found to cause severe viral infections (including
coronaviruses and influenza) in some affected individuals15. Alternatively, gene dose can also impact disease
phenotype and severity, in diseases that are classically described as AR disorders. An example of this
phenomenon are mutations in RAG1, in which biallelic LOF mutations classically cause SCID, but patients with
biallelic hypomorphic mutations can present later in life with combined immunodeficiency or milder immune
dysregulation depending on residual RAG activity16,17. These findings challenge the assumption that IEI are
inevitably ultrarare and severe diseases affecting primarily children, rather they may include more common
disorders that can present across the lifespan or even exclusively after exposure to specific microorganisms18.
Because of the expanding phenotypes, we have updated tables with less restrictive titles, and we foresee that
current classifications may have to be reconsidered as the spectrum of disease associated with individual genes
can be diverse.
Clinically and phenotypically distinct IEI can arise due to variants in the same gene that have divergent
molecular mechanisms such as LOF, GOF, neomorphic or multimorphic function. Examples of this are mutations
in IRF4, with one new entry causing AD combined immunodeficiency (Table I, sub table 3) due to a mutation
resulting in a neomorphic function19 and two entries in Table VI, sub-table 9 causing either Whipple disease by
haploinsufficiency or antibody deficiency by another AD neomorphic variant19-21. Similarly, CARD11 has three
entries in three different tables as different inheritance patterns and pathogenic mechanisms lead to distinct
phenotypes. OTULIN also appears 3 times - all in Table VII sub-table 3 - due to distinct mechanisms of disease
(heterozygous dominant negative or haploinsufficiency; AR LOF) that still manifest with similar clinical
phenotypes. STAT1 and STAT3 have different entries in different tables because mutations in these genes lead to
dramatically different phenotypes by GOF or LOF. This also emphasizes the crucial need to undertake in-depth
in vitro functional validation of any novel variant considered to be potentially pathogenic. As a result, in this
current update, more than 40 genes have more than one entry either in the same table or in different tables.
Considering this complexity, counting IEI has become increasingly difficult. To improve clarity, for this version,
we decided to count the number of monogenic IEI conditions and separately, the number of genes associated to
disease. If mutations in a gene cause disease with a similar phenotype yet following a AR / AD inheritance pattern,

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they were counted as one condition. If the diseases caused by a pathogenic variant in a single gene following
AR/AD inheritance expresses with a different phenotype, they are counted as two different conditions. With
evolving genetic and pathophysiological insight, the number of IEI may slightly change in the future as some
conditions might be considered a spectrum of one disease rather than truly different conditions. As a result,
comparing the numbers to previous versions would not be accurate as the criteria for counting are continuously
evolving.
The discovery of novel IEI continues to demonstrate that distinct variants or zygosity in the same gene
can cause disparate clinical conditions. In the current update, UNC93B1 is an example. Whereas AR UNC93B1
LOF was identified previously as an IEI underlying herpes simplex encephalitis, recent findings link heterozygous
UNC93B1 GOF variants to childhood onset systemic lupus erythematosus (SLE)22,23; furthermore, mouse models
have revealed a gene dosage effect of Unc93b1 GOF variants24.

Novel IEIs
Since the last update in 202212, novel gene defects have been found for most categories of IEI, including novel
causes of:
• Combined immunodeficiencies: IRF4, NFATC1, PRIM1, FOXI3, POLD3, NUDCD3, PSMB1019,25-31 (Table
1, Supplementary Table 1
• Combined immunodeficiencies with syndromic features: Dominant negative (DN) IKZF2, GINS4, STAT6-
GOF, SLC19A1, SGPL1, PTCRA, FLT3L, ITPR3, RECQL432-43 (Table 2, Supplementary Table 1)
• B-cell deficiencies, agammaglobulinemia or hypogammaglobulinemia PAX5, KARS144,45(Table 3,
Supplementary Table 1)
• Immune dysregulation: CD274 (PDL1), TLR7 GOF, UNC93B1 GOF, TRAF3, CBLB, PLCG1, SH2B3,
ARPC5, NFATC2, DOCK11, RHBDF2, LACC1, ERN1, NBEAL2 ,IL27RA, TNFSF9, DPP9, GIMAP622,24,46-
66
(Table 4, Supplementary Table 1)
• Neutropenia: DBF4, SRP19, SRPRA, CCR267-69 (Table 5, Supplementary Table 1)
• Innate immune defects resulting in susceptibility to mycobacterial/bacterial (IRF1, MCTS170,71) and viral
(OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, IKBKE72-77) infections (Table 6, Supplementary Table
1)
• Autoimmune/autoinflammatory disorders: STAT4 GOF, PMVK, ALPK1, LYN, SHARPIN, LSM11, RNU71,
OTULIN, RELA78-87. Heterozygous LOF variants in RELA have been previously described causing
mucocutaneous inflammation and fever but are included as a new disease in this update as novel descriptions of
DN mutations are associated with an inflammatory phenotype driven by TLR7 upregulation and enhanced
secretion of interferons. (Table 7, 10, Supplementary Table 1). Specific c.61G>C variants in NLRP3 are noted to
cause keratitis fugax hereditaria.88,89

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• Bone marrow failure: SNM1B, DUT, RAD50 90-92 (Table 9, Supplementary Table 1)
• Phenocopies of IEI: a somatic variant in JAK193 93 and auto antibodies against IL-27 63(Table 10, Supplementary
Table 1)
New entries for each table below are depicted in bold.

Phenocopies of known IEIs confirm critical pathways for immune function

Some of these novel genetic findings link common clinical phenotypes that converge on a shared pathway.
Examples in this update include the following:
• PRIM1 encodes the catalytic subunit of the DNA primase as part of the DNA polymerase complex that includes
POLA1 and POLD, mutations in which are associated with immunodeficiency and distinct syndromic features.
Biallelic mutations in PRIM1 cause primordial dwarfism characterized by growth retardation, microcephaly, and
developmental delay with B cell deficiency, but unlike patients with defects in POLA1 and POLD have normal
T cell numbers with conserved proliferation27.
• GINS4 is a component of the DNA replication machinery of mammalian cells and forms part of
multimeric/multiprotein “replisome” complexes94. Biallelic mutations in GINS4 result in a clinical phenocopy of
AR deficiency of MCM10, MCM4 or GINS1 genes33,95,96 that encode key proteins involved in DNA replication94.
• Description of AR PMVK deficiency, which functions upstream of MVK, confirms the pathogenic effect of
disturbed mevalonate metabolism, resulting in an autoinflammatory disease81.
• Recently described NUDCD3-deficiency builds on the crucial role of RAG-mediated recombination, with
pathologic sequestration of RAG1 in the nucleoli in the absence of NUDCD330.

IEIs define specific roles for known genes and reveal immune-specific functions of novel genes
Unlike mouse models or complementary to mouse models, the description of patients with IEIs and study of the
pathogenic mechanism of IEIs can demonstrate non-redundant as well as redundant functions of a specific gene
in human immunity. Examples are as follows:
• NUDCD3 was mostly known as a chaperone protein, with only hints to a potential role in the immune system
through interactome studies. We have now learned that it plays a crucial role in optimal localization of RAG1
necessary for recombination of T cell and B cell antigen receptors30.
• Studies in mice have established that FLT3L functions as a hematopoietic factor essential for the development
of natural killer (NK) cells, B cells, and dendritic cells (DCs) 97,98. The identification of three patients with AR
FLT3L deficiency confirmed that FLT3L is also required for B cell and DC development humans. However,
unlike mice, human FLT3L is required for the development of monocytes but not NK cells99.
• Study of patients with PTCRA variants taught us that, unexpectedly, the majority have remained healthy at ages
2 to 65 years whereas others had severe infection, lymphoproliferation or autoimmunity, developing during

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adolescence or adulthood. Further investigation of individuals with hypomorphic PTCRA variants showed that
memory αβ T cells can develop in the absence of human pre-TCRα and that human pre-TCRα is largely redundant
for αβ T cell development. However complete or partial deficiency can lead to late onset clinical manifestations,
with incomplete penetrance39.
• PSMB10 was previously described as an AR disease gene for the autoinflammatory disorders PRAAS5 but
specific, sporadic heterozygous variants in the same gene are clearly associated rather with a SCID/Omenn
phenotype. The distinct behaviour of such variants is not yet understood in terms of pathomechanism31.

Recently identified IEIs have also revealed critical roles for genes in new disease contexts. For instance,
our previous update highlighted the role of the type I IFN pathway in host defence against SARS-CoV-2 with the
identification of germline defects in this pathway or autoantibodies against type I IFNs associated with severe
12
COVID-19. Subsequent studies related to the COVID pandemic have included children presenting with
multisystemic inflammatory syndrome (MIS-C) after SARS COV-2 infection and uncovered autosomal recessive
deficiencies of OAS1, OAS2, or RNASEL in around 1% of patients with this severe inflammatory complication.
These gene products function in the same signalling pathway and to suppress inflammation after double-stranded
RNA–detection. Thus, AR OAS1, OAS2, and RNASEL deficiencies result in uncontrolled inflammatory
cytokine production that can underlie inflammation in some patients.72
The role of autoantibodies in susceptibility to infections is a growing field. The identification of
neutralizing autoantibodies against different cytokines have explained some aspects of the complex phenotypes
of immune dysregulation in previously described IEIs, such as those affecting the alternative NF-B pathway100.
In this update, we include autoantibodies directed against IL-27 underlying EBV infections63 , which phenocopies
AR variants in IL27RA encoding one component of the IL-27R complex.

Somatic mutations as a phenocopy of IEI

Advances in sequencing techniques and analysis have enabled the identification of somatic variants as a cause of
human immune diseases. Since IEIs have been defined as being caused by monogenic germline mutations,
somatic mutations associated with disease are classified in Table X along with the phenocopies of IEI. Several of
these somatic disorders have no germline disease equivalent. This is the case for VEXAS (acronym for vacuoles,
E1 ligase, X-linked Autoinflammatory syndrome) due to somatic mutation in UBA1 causing X-linked typically
adult-onset immune dysregulation101. In addition, there are diseases caused by either germline or somatic
mutations including autoimmune lymphoproliferative syndrome (ALPS) due to FAS-FASL or RALD for which
somatic mutations represent an important proportion of affected patients. All these disorders are included as
phenocopies in Table X. In this update, for several previously described autosomal dominant autoinflammatory
disorders, somatic mutations have been found to underlie a phenotype closely resembling that of germline variants

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affecting the same gene. Such is the case for somatic mutations in NLRP3, NOD2, TNFRSF1A, TNFAIP3, NLRC4,
and MEFV102-107. This growing list of immune disorders caused by somatic mutations underscores the need to
consider variants detected at low allelic frequencies as possibly disease causing, stressing the need for clinical
laboratories to find ways to report these occurrences in addition to germline variants. We foresee that this list of
somatic disorders resembling their IEI counterparts will increase with further advances in genetic sequencing and
analysis techniques108. In consideration of this, and to avoid redundancy, this committee has decided to denote
such disorders throughout the manuscript to alert to the possibility of mosaicism as opposed to including them in
Table X as different disorders.

Autoinflammation and immune dysregulation are at the forefront of novel discoveries blurring the borders
between immunodeficiencies and rheumatology
Among the newly described genes almost half (46%, 29/63) are either in the autoinflammatory or immune
dysregulation tables. Autoimmune diseases affect around 10% of the population worldwide109. These diseases
have a complex etiology where genetic and environmental factors interact, leading to a loss of tolerance against
self-antigens, subsequent inflammation, and end organ damage. B cell dysregulation strongly contributes to the
pathogenesis of several autoimmune diseases including SLE. The identification of new causes of monogenic
lupus furthers our knowledge on how B cells are dysregulated and sheds light on new therapeutic targets. In this
update two novel gene defects are associated with monogenic lupus, namely GOF variants in TLR7110 or
UNC93B122,23. Remarkably, UNC93B1 is upstream of TLR7 and UNC93B1 GOF results in TLR7
hyperactivation, while TLR7 GOF variants result in aberrant survival of activated B cells. In addition, mutations
in ERN1 (encoding IRE1) disrupt XBP1 splicing and are associated with autoimmunity including SLE in one
family member61. In this update, we also include LACC1 as a monogenic cause of arthritis59. Similar to COPA
syndrome111, monogenic arthritis due to biallelic LOF LACC1 variants is indistinguishable from polygenic
arthritis. Thus, the identification of monogenic causes of arthritis may contribute to understanding
pathophysiology and uncover new possibilities for precision medicine in rheumatology. As evidenced by the
growing list of monogenic autoimmune disorders, the field of IEIs has become increasingly intertwined with
rheumatology, underscoring the need to consider genetic analysis of patients with rheumatologic disease
especially with, but not solely, onset in childhood. On the other hand, it is important to note that the phenotypes
of IEIs in general and specifically IEIs associated with autoimmunity and autoinflammation are increasingly
overlapping.

Conclusions
In this update, the IUIS Expert Committee on IEI reports on 63 novel IEIs. These new gene defects bring the total
number of IEIs to 555 (including 4 CNVs) with variants in 504 genes. (Figure 1A, B). The goals of the IUIS

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Expert Committee on IEI are to increase awareness, facilitate recognition, promote optimal treatment, and support
research in the field of clinical immunology. The continuous increase in novel IEIs highlights the power of next-
generation sequencing technologies with increased read depth also allowing for the detection of somatic
mutations. Thorough and rigorous validation of candidate pathogenic variants enables us to (1) identify novel
gene defects underlying human disease, (2) unveil pathogenic mechanisms, (3) define non-redundant functions
of key genes in human immune cell development, host defence, and immune regulation, (4) expand the
immunological and clinical phenotypes of IEIs, and (5) allow for future development of pathway- or gene-specific
therapies. Collectively, the contributions of the researchers and scientists who discover novel IEIs will not only
aid in diagnosing additional patients but also add to our fundamental knowledge of human immunology.

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Table I: Immunodeficiencies affecting cellular and humoral immunity

1. T-B+ Severe Combined Immune Deficiency (SCID)

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
c deficiency (common gamma chain Very low Normal to high Low Low NK
IL2RG XL 308380
SCID, CD132 deficiency)
JAK3 deficiency JAK3 AR 600173 Very low Normal to high Low Low NK
IL7R deficiency IL7R AR 146661 Very low Normal to high Low Normal NK
CD45 deficiency PTPRC AR 151460 Very low Normal Low Normal / T cells
CD3 deficiency CD3D AR 186790 Very low Normal Low Normal NK, no / T cells
CD3 deficiency CD3E AR 186830 Very low Normal Low Normal NK, no / T cells
CD3 deficiency CD247 AR 186780 Very low Normal Low Normal NK, no / T cells
Coronin-1A deficiency CORO1A AR 605000 Very low Normal Low Detectable thymus
Normal to Typical SCID or combined
low ‘Normal to low High immunodeficiency, the latter with
LAT deficiency LAT AR 602354
adenopathy, splenomegaly,
recurrent infections, autoimmunity
Reduced Normal High IgM, Early-onset skin abscesses, rash,
SLP76 deficiency LCP2 AR 619374
low IgA recurrent infections, autoimmunity

2. T-B- SCID
Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features

RAG1 179615 Normal NK cell number, but

RAG deficiency Very low Very low Decreased increased risk of graft rejection,
RAG2 AR 179616 possibly due to activated NK cells
Very low Very low Decreased Normal NK cell number, but
increased risk of graft rejection,
DCLRE1C (Artemis) deficiency DCLRE1C AR 605988
possibly due to activated NK cells,
radiation sensitivity
Very low Very low Variable Normal NK, radiation sensitivity,
DNA PKcs deficiency PRKDC AR 615966
microcephaly
Very low Very low Decreased Normal NK, radiation sensitivity,
Cernunnos/XLF deficiency NHEJ1 AR 611290
microcephaly
Very low Very low Decreased Normal NK, radiation sensitivity,
DNA ligase IV deficiency LIG4 AR 601837
microcephaly
Very low Low, decreasing Low, Low NK, bone defects, may have
Adenosine deaminase (ADA) deficiency ADA AR 608958 decreasing pulmonary alveolar proteinosis,
cognitive defects
Very low Very Low Decreased Reticular dysgenesis with
AK2 defect AK2 AR 103020
neutropenia; deafness

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 Low, poor Recurrent bacterial and viral
Very low Very Low specific infections, lymphoproliferation;
Activated RAC2 defect RAC2 AD GOF 602049
antibody neutropenia
responses
Omenn syndrome, abnormal VDJ
NUDCD3 deficiency NUDCD3 AR NA Very low Very low Decreased
recombination

3. Combined Immunodeficiency (CID), Generally Less Profound than SCID

T cells B cells Ig Associated features
Disease Genetic defect Inheritance OMIM
Severe and opportunistic infections, idiopathic neutropenia;
CD40 ligand
hepatitis and cholangitis, Cryptosporidium infections,
(CD154) CD40LG XL 308230
cholangiocarcinoma; autoimmune blood cytopenias; peripheral
deficiency
Normal to low neuroectodermal tumors
Normal sIgM+IgD+ Neutropenia, opportunistic infections, gastrointestinal and
naïve B cells IgM normal or high, biliary tract and liver disease, Cryptosporidium infections
present; other Ig isotypes low
CD40 IgG+, IgA+,
CD40 AR 606843
deficiency IgE+
memory B
cells absent

ICOS Normal Normal Low Recurrent infections, autoimmunity, gastroenteritis,

ICOS AR 604558
deficiency granulomas
ICOSL Low Low Low Recurrent bacterial and viral infections, neutropenia
ICOSLG AR 605717
deficiency
CD3 Normal number, but Normal Normal Immune deficiency and autoimmunity of variable severity
CD3G AR 186740
deficiency low TCR expression
CD8 Absent CD8, Normal Normal Normal Recurrent infections, may be asymptomatic
CD8A AR 186910
deficiency CD4
ZAP-70 Low CD8 number, Normal Normal May have immune dysregulation, autoimmunity
deficiency ZAP70 AR 269840 normal CD4 number
(ZAP70 LOF) but with poor function
ZAP-70 Normal IgA, low
combined Normal or IgM, low/normal Severe autoimmunity (bullous pemphigoid, inflammatory colitis
Decreased CD8,
hypomorphic decreased IgG; protective Ab
ZAP70 AR (LOF/GOF) 617006 normal or decreased
and responses to
CD4 cells
activating vaccines
mutations
TAP1 AR 170260
Vasculitis, pyoderma gangrenosum
MHC class I TAP2 AR 170261
Low CD8, normal
deficiency TAPBP AR 601962 CD4, absent MHC I on Normal Normal
lymphocytes Sinopulmonary infections, cutaneous granulomas. Absent β2m
B2M AR 109700
associated proteins MHC-I, CD1a, CD1b, and CD1c

Page 12 of 79
 CIITA AR 600005 Low CD4+ T cells, Failure to thrive, respiratory and gastrointestinal infections,
MHC class II reduced MHC II liver/biliary tract disease
RFXANK AR 603200
deficiency expression on Normal Normal to low
group A, B, RFX5 AR 601863 lymphocytes
C, D RFXAP AR 601861
IKAROS no memory T cells no memory Low Ig, Recurrent sinopulmonary infections, pneumocystis early CID
IKZF1 AD DN 603023
deficiency B cells onset
T cell lymphopenia, increased Low IgM, Low NK cells with poor function. Eosinophilia, recurrent
reduced naïve CD8 T total B cells, normal/high IgG and infections, cutaneous viral, fungal, and staphylococcal
cells, increased reduced IgA, very high IgE, infections, severe atopy/allergic disease, cancer diathesis
exhausted CD8+ TEM memory B poor antibody
DOCK8
DOCK8 AR 243700 cells, reduced MAIT, cells Poor responses
deficiency
NKT cells, increased peripheral B
 cells; poor cell
proliferation; few Treg tolerance.
with poor function
Early invasive herpes viral, bacterial infections, Normal NK cell
DOCK2 IgG normal or low, number, but defective function. Poor interferon responses in
DOCK2 AR 603122
deficiency poor antibody hematopoietic and non-hematopoietic cells
Low Normal
responses
174761 Low B cells Recurrent respiratory tract infections, skin infections, warts and
POLD1
AR but normal molluscum, short stature, intellectual disability
Low CD4 T cells Low IgG
Polymerase  POLD2 600815 maturation
deficiency Low IgG and IgA, Recurrent infections and Omenn´s syndrome, athymia
Low naïve CD4 T
POLD3 AR NA Normal normal IgM, high
cells
IgE
Prominent forehead, microcephaly, triangular face,
hypertelorism, small low-set ears, flat nasal bridge,
Low or absent straight horizontal and bilateral cryptorchidism. Hepatic
PRIM1 PRIM1 AR 620005 Normal Low B cells
immunoglobulins fibrosis, variable basal ganglia calcification. Growth
failure. Recurrent neumonias, GI and systemic
infections. type I interferon signature.
Normal, few naïve T HPV infection, lung granulomas, molluscum contagiosum,
RHOH cells, restricted Normal Normal lymphoma
RHOH AR 602037
deficiency repertoire, poor
proliferation to CD3
CD4 lymphopenia, Intermittent neutropenia, bacterial, viral (HPV, EBV,
reduced naïve T cells, Reduced IgM, molluscum), candidal infections, lymphoproliferation,
STK4
STK4 AR 614868 increased TEM and Reduced increased IgG, IgA, autoimmune cytopenias, lymphoma, congenital heart disease
deficiency
TEMRA cells, poor memory B IgE; impaired Ab
proliferation cells responses
Absent TCRαβ except
for a minor CD3-dim Recurrent viral, bacterial, fungal infections, immune
TCRα
TRAC AR 615387 TCRαβ population; Normal Normal dysregulation and autoimmunity, diarrhea
deficiency
most T cells γδ; poor
proliferation

Page 13 of 79
 Low CD4+, low Treg,
LCK restricted T cell Normal Normal IgG and IgA, Recurrent infections, immune dysregulation, autoimmunity
LCK AR 615758
deficiency repertoire, poor TCR high IgM
signaling
Progressive CD4 T cell EBV associated B cell lymphoproliferation, lymphoma, immune
ITK
ITK AR 186973 lymphopenia; reduced Normal Normal to low serum dysregulation
deficiency
T cell activation Ig
Normal number, poor Normal levels, poor Bacterial, fungal, and viral infections
MALT1
MALT1 AR 615468 proliferation Normal specific antibody
deficiency
response
Normal number, Normal, Pneumocystis jirovecii pneumonia, bacterial and viral infections
predominantly naïve T- transitional Absent/low
CARD11
CARD11 AR LOF 615206 cells, poor proliferation B cell
deficiency
predominan
ce
Normal number, few Normal Recurrent bacterial and viral infections, candidiasis,
memory T and Treg number, gastroenteritis
BCL10 cells, poor antigen and decreased Low
BCL10 AR 616098
deficiency anti-CD3 proliferation memory and
switched B
cells
Normal number, Low, Hypogammaglobulin Severe early onset colitis, recurrent sinopulmonary infections
normal/low function decreased emia, poor specific
IL-21
IL21 AR 615767 memory and antibody responses;
deficiency
switched B increased IgE
cells
Normal number, low Normal, Recurrent infections, Pneumocystis jiroveci, Cryptosporidium
cytokine production, decreased infections, liver disease
IL-21R
IL21R AR 615207 poor antigen memory and
deficiency
proliferation switched B
cells
Normal numbers, low Normal Impaired immunity to HHV8, Kaposi’s sarcoma
OX40 antigen specific numbers, Normal
TNFRSF4 AR 615593
deficiency memory CD4+ low memory
B cells
Normal number, Normal Recurrent bacterial, viral, fungal infections, opportunistic
IKBKB absent Treg and / T number, Low infections
IKBKB AR 615592
deficiency cells, impaired TCR poor
activation function
Normal number, poor Low, low Low NK number and function, recurrent bacterial, viral and
NIK proliferation to antigen switched Low Ig’s Cryptosporidium infections
MAP3K14 AR 604655
deficiency memory B
cells
Normal number, poor Normal Ig levels but
RelB
RELB AR 604758 diversity, reduced Marked Impaired specific
deficiency
proliferation to increase in antibody responses Recurrent infections

Page 14 of 79
 mitogens; no response B cell
to Ag number
Normal number, Low number Low Ig’s over time Recurrent infections with bacteria, varicella, neutropenia
Moesin
MSN XL 300988 defective migration,
deficiency
proliferation
Normal number, poor Normal Low Recurrent infections, neutropenia, thrombocytopenia
TFRC proliferation number, low
TFRC AR 616740
deficiency memory B
cells
Normal, decreased Low, mostly Low, poor specific Recurrent infections with bacteria, mycobacteria, salmonella,
memory CD4, poor naïve; few antibody responses and opportunistic organisms. Defective innate immunity
proliferation switched
c-Rel
REL AR 164910 memory B
deficiency
cells,
impaired
proliferation
Recurrent infections (viral, mycobacteria, bacterial, fungal),
FCHO1 lymphoproliferation, failure to thrive, increased activation-
FCHO1 AR 613437
deficiency Low, poor proliferation Normal Normal induced T-cell death, defective clathrin-mediated endocytosis
number
severe T cell Omenn-like syndrome (erythroderma, lymphocytosis,
PAX1 lymphopenia, low Normal Normal eosinophilia, severe/recurrent infections), no thymus, T cell
PAX1 AR 615560
deficiency TRECs number deficiency not corrected by HSCT. Otofaciocervical syndrome
type 2, ear abnormalities
ITPKB Very few T cells Normal Normal IgM, A; low FTT, recurrent bacterial/fungal infections, pan-leukopenia,
ITPKB AR NA
deficiency IgG anemia, thrombocytopenia
SASH3 T/NK cell lymphopenia B cell Low, poor specific Recurrent sinopulmonary, cutaneous and mucosal infections,
SASH3 XL NA
deficiency lymphopenia antibody responses refractory autoimmune cytop/neutropenia
MAN2B2 Low T cells Low B cells Normal/low Recurrent infections, vasculitis, arthritis, FTT, microcephaly,
MAN2B2 AR NA
deficiency neurodevelopmental delay; congenital disorder of glycosylation
T cell lymphopenia Normal Normal but poor Ig Recurrent pneumonia, viral respiratory infections, chronic EBV,
COPG1
COPG1 AR NA response to CMV viremia, FTT, bronchiectasis
deficiency
vaccines
Increased activated T Normal Reduced Recurrent upper respiratory infections/pneumonia, thrush,
HELIOS AD cells number; mucosal ulcers, chronic lymphadenopathy, SLE, ITP, AIHA
IKZF2 NA
deficiency AR reduced (Evan’s syndrome), EBV-associated HLH, lymphoma
memory
IKK Normal Reduced Low Recurrent bacterial, viral, fungal infections, absent secondary
CHUK AR NA
deficiency lymphoid tissues; skeletal abnormalities, FTT
Normal counts of Reduced Agammaglobuline Early onset recurrent sinopulmonary infections
circulating T cells; CD19+ mia or extremely with Pneumocystis jirovecii, pneumonia, severe viral
IRF4 normal proportions cells; low IgM, IgG, and disease (CMV and EBV), localized disease with weakly
multimorphic IRF4 AD-neomorph NA of naïve, CM, EM and increased IgA serum levels, virulent (BCG vaccine) or pathogenic mycobacteria (M.
(IRF4 R95T) TEMRA CD4+ T cells, naïve B bovis), and chronic diarrhea.
reduced CM, EM, cells,
TEMRA CD8+ T cell reduced

Page 15 of 79
 proportions; low class-
TH17 and TFH cells switched
memory B
cells, and
decreased
plasmablas
ts and
plasma
cells.

Lymphocytes, low hypogammaglobulinemia, low IgM, IgG, and IgA serum levels,
Primary
naïve CD4 and CD8 T early gray haring.
Antibody
IRF4 AD-neomorph NA cell counts and high
deficiency/CI
terminal effector CD4
D due to IRF4
and CD8 T cell counts
normal increased Normal, Hypogammaglobul Early onset sinopulmonary infections with bronchiectasis.
proportions of CD8+ lower inemia, decreased May present with recurrent warts, bacterial skin infections
T, lower proportions proportions or normal serum (folliculitis and abscesses). Scoliosis in 2 of 3 .pts.
of naïve and CM of IgA, decreased
CD4+ and CD8+ T switched- serum IgG and
NFATC1
NFATC1 AR NA cells, increased CM T memory IgM, low titers to
deficiency
cells; lower and pneumococcus
proportions of Treg, increased and HBV vaccines
TFH, TH1, TH2 proportions
of naïve B
cells
FOXI3 CD4 and CD8 T cell Slightly Normal Abnormal TRECS, thymus hypoplasia; increased head
Haploinsuffici FOXI3 AD NA lymphopenia decreased circumference.
ency
PSMB10 Low, skewed TCR Low or Low Omenn syndrome (diarrhea, alopecia, rash). Severe and
PSMB10
associated repertoire. Low absent recurrent infections (candidiasis, disseminated VZV and
p.Asp56His/p. AD
Omenn TRECs CMV, pneumocystis pneumonia, skin infections).
Gly201Arg
Syndrome Hypereosinophilia.

SCID/CID spectrum: Infants with SCID who have maternal T cell engraftment may have T cells in normal numbers that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease.
Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID, or still less profound combined immunodeficiency (CID) phenotypes. Both OS and leaky SCID
can be associated with >300 autologous T cells/uL of peripheral blood and reduced, rather than absent, proliferative responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings
including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4 T lymphopenia can be found in an allelic series of RAG1/2 and other SCID-associated genes. There can be clinical
overlap between some genes listed here and those listed in Table VII.

SCID severe combined immunodeficiency, CID combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, XL X-linked
inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function, FTT: failure to thrive

Total number of mutant genes Table I: 73 (ZAP70 has two entries with different inheritance mechanisms and associated phenotypes, thus two different disorders)

New inborn errors of immunity: 7; IRF4, NFATC1, PRIM1, FOXI3, POLD3, NUDCD, PSMB10 19,25-31

Page 16 of 79
Page 17 of 79
Table II: Combined immunodeficiencies with associated or syndromic features

1. Immunodeficiency with Congenital Thrombocytopenia

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
Thrombocytopenia with small
platelets, eczema, recurrent
Low IgM and antibody bacterial/viral infections, bloody
Progressive decrease in responses to diarrhea, lymphoma, autoimmune
Wiskott-Aldrich syndrome numbers, abnormal Normal numbers polysaccharides, often disease, IgA- nephropathy. Patients
WAS XL 300392
(WAS LOF) lymphocyte responses high IgA and IgE with XL-thrombocytopenia have later
to anti-CD3 onset of complications and more
favourable life expectancy but
eventually develop similar
complications as observed in WAS
Reduced, defective Thrombocytopenia with or without
lymphocyte responses Normal or low Normal, except for high small platelets, recurrent bacterial and
WIP deficiency WIPF1 AR 602357
to anti-CD3 IgE viral infections, eczema, bloody
diarrhea; WAS protein absent
Mild thrombocytopenia with normal
Normal except for high sized platelets, recurrent invasive
Arp2/3-mediated filament Normal Normal numbers IgA and IgE infections; colitis, vasculitis,
ARPC1B AR 604223
branching defect autoantibodies (ANA, ANCA),
eosinophilia; defective Arp2/3 filament
branching
Recurrent respiratory and ear
infections, pneumonia, and chronic
lung disease. Early-onset immune
dysregulation (atopic dermatitis
CD4 and CD8 T cell Normal or low.
and AIHA) and syndromic features
IKZF2 DN (ICHAD syndrome) IKZF2 AD 606234 lymphopenia with low Normal to low Response to vaccine
including developmental delay,
TRECs antigen normal to low
autism, sensorineural hearing loss,
cleft palate and syndromic
craniofacial features, abnormal
teeth, atelia (absent nipples).

Page 18 of 79
 2. DNA Repair Defects Other Than Those Listed in Table 1
Disease Genetic Inheritance OMIM T cells B cells Ig Associated features
defect
Ataxia-telangiectasia ATM AR 607585 Progressive Normal Often low IgA, IgE and IgG Ataxia, telangiectasia especially of sclerae;
decrease, poor subclasses, increased IgM pulmonary infections; lymphoreticular and other
proliferation to monomers; antibodies malignancies; increased alpha fetoprotein;
mitogens; may variably decreased increased radiosensitivity, chromosomal
have low TRECs instability and chromosomal translocations
and T cells by
newborn screening
(NBS)
Nijmegen breakage syndrome NBN AR 602667 Progressive Variably Often low IgA, IgE, and IgG Microcephaly, dysmorphic facies; lymphomas
decrease; may reduced subclasses, increased IgM; and solid tumors; increased radiosensitivity;
have low TRECs antibodies variably chromosomal instability
and T cells by NBS decreased
Bloom syndrome BLM AR 604610 Normal Normal Low Short stature, dysmorphic facies sun-sensitive
erythema; marrow failure; leukemia, lymphoma;
chromosomal instability
602900 Decreased or Facial dysmorphic features, developmental delay,
normal, responses macroglossia; bacterial/opportunistic infections;
DNMT3B AR to PHA may be malabsorption; cytopenias; malignancies;
decreased multiradial configurations of chromosomes 1, 9,
Immunodeficiency with Decreased Hypogammaglobulinemia or 16
centromeric instability and facial ZBTB24 AR 614064 Decreased or or normal agammaglobulinemia,
anomalies normal variable antibody deficiency
(ICF types 1, 2, 3, 4) CDCA7 AR Decreased or Facial dysmorphic features, macroglossia;
609937 normal; responses bacterial/opportunistic infections; malabsorption;
to PHA may be cytopenias; malignancies; multiradial
decreased configurations of chromosomes 1, 9, 16
HELLS AR 603946 Decreased or
normal
PMS2 Deficiency PMS2 AR 600259 Normal Low B Low IgG and IgA, high IgM,
cells, abnormal antibody
switched responses Recurrent infections ; café-au-lait spots;
and non- lymphoma, colorectal carcinoma, brain tumors
switched
RNF168 deficiency RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to
(Radiosensitivity, Immune ataxia; normal intelligence to learning difficulties;
Deficiency, Dysmorphic features, mild facial dysmorphism to microcephaly;
Learning difficulties [RIDDLE] increased radiosensitivity
syndrome)
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function; viral
infections (EBV, HSV, VZV); short stature; B cell
lymphoma; adrenal failure

Page 19 of 79
X-linked reticulate pigmentary POLA1 XL 301220 Not assessed Not Not assessed Hyperpigmentation, characteristic facies, lung,
disorder (POLA1 deficiency) assessed and GI involvement. NK cell dysfunction.
Recurrent viral infections. POLA1 is required for
synthesis of cytosolic RNA:DNA, its deficiency
leads to increased type I interferon, hypomorphic
variants may present with hyperpigmentation and
interferonopathy, without immunodeficiency.

POLE1 (Polymerase ε subunit 1) POLE1 AR 174762 Normal; decreased Low Low IgG2 and IgM, lack of Recurrent respiratory infections, meningitis; facial
deficiency (FILS syndrome) T cell proliferation memory B antibody to PPS dysmorphism, livedo, short stature
cells
POLE2 (Polymerase ε subunit 2) POLE2 AR 602670 Lymphopenia, lack Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG
deficiency of TRECS at NBS, infections; autoimmunity (type 1 diabetes),
absent proliferation hypothyroidism, facial dysmorphism
in response to
antigens
Ligase I deficiency LIG1 AR 126391 Lymphopenia, Normal Hypogammaglobulinemia, Recurrent bacterial and viral infections; growth
increased γδ T Reduced antibody retardation; sun sensitivity, radiation sensitivity;
cells, decreased responses macrocytic red blood cells
mitogen response

NSMCE3 deficiency NSMCE3 AR 608243 Decreased Normal Normal IgG, IgA, normal to Severe lung disease (possibly viral); thymic
number, poor elevated IgM; decreased hypoplasia; chromosomal breakage, radiation
responses to antibody responses to PPS sensitivity
mitogens and
antigens
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly; bone marrow
failure
GINS1 deficiency GINS1 AR 610608 Low or normal Low or High IgA, low IgM, and IgG Neutropenia; IUGR; NK cells very low
normal
MCM10 deficiency MCM10 AR 619313 Low or normal Low Normal IgM, IgA, decreased Severe (fatal) CMV infection, HLH-like,
IgG phenocopies GINS1 and MCM4 deficiencies; 
NK cells and NK function
GINS4 deficiency GINS4 AR 610611 Normal Normal Normal or increased Low NK cell numbers and function,
neutropenia, recurrent infections including
CMV and varicella, and recurrent herpes
labialis; recurrent otitis, sinusitis, gingivitis
and oral abscesses, pneumonia,
gastrointestinal sepsis, intermittent diarrhea,
intrauterine growth restriction, growth delay,
cryptorchidism, tonsillar hypertrophy,
recurrent fever.
Rothmund-Thomson syndrome RECQL4 AR 268400 Normal or low Normal or Normal or low Variable immunodeficiency, recurrent
low infections, poikiloderma, hyperkeratosis, hair,
skeletal dental and gastrointestinal

Page 20 of 79
 abnormalities, growth delay, increased
cancer risk, especially osteosarcoma

3. Thymic Defects with Additional Congenital Anomalies

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
DiGeorge/velocardio- Decreased or normal,
Large deletion (3Mb)
facial syndrome 5% have low TRECs at
typically in
Chromosome 22q11.2 AD 602054 NBS and <1500 CD3T
chromosome 22
deletion syndrome cells/µL in neonatal
(TBX1)
(22q11.2DS) period Hypoparathyroidism; conotruncal cardiac
DiGeorge/velocardio- Decreased or normal Normal Normal or decreased malformation, velopalatal insufficiency; abnormal
Unknown Sporadic facies; intellectual disability
facial syndrome
Decreased or normal,
TBX1 deficiency TBX1 AD 602054 may have low TRECs at
NBS
CHD7 AD 608892 Decreased or normal, Coloboma of eye; heart anomaly; choanal atresia;
may have low TRECs at Normal Normal or decreased intellectual disability; genital and ear anomalies, CNS
CHARGE syndrome SEMA3E AD 608166
NBS; response to PHA malformation; some are SCID-like
Unknown may be decreased
Very low Normal Decreased Severe infections; abnormal thymic epithelium,
Winged helix nude
FOXN1 AR 601705 immunodeficiency; congenital alopecia, nail
FOXN1 deficiency
dystrophy; neural tube defect
Severe T cell Normal/ Not assessed Recurrent, viral, and bacterial respiratory tract
FOXN1
FOXN1 AD 600838 lymphopenia at birth, low infections; skin involvement (eczema, dermatitis), nail
haploinsufficiency
normalised by adulthood dystrophy
Normal, rarely Hypoparathyroidism; renal disease; deafness; growth
lymphopenia and Normal Normal retardation; facial dysmorphism; cardiac defects may
Chromosome 10p13- decreased be present; recurrent infections +/-
p14 deletion syndrome Del10p13-p14 AD 601362 lymphoproliferation to
(10p13-p14DS) mitogens and antigens;
hypoplastic thymus may
be present
Decreas Hypogammaglobuline Recurrent respiratory infections; multiple warts; facial
Lymphopenia; low NK ed B mia, decreased dysmorphism, growth retardation
Chromosome 11q
cells cells and antibody responses
deletion syndrome 11q23del AD 147791
switched
(Jacobsen syndrome)
memory
B cells

4. Immuno-osseous Dysplasias
Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features

Page 21 of 79
 Varies from Normal Normal or reduced, Short-limbed dwarfism with metaphyseal dysostosis;
severely decreased antibodies variably sparse hair; bone marrow failure; autoimmunity;
Cartilage hair hypoplasia 157660 (SCID) to normal; decreased susceptibility to lymphoma and other cancers;
RMRP AR
(CHH) impaired impaired spermatogenesis; neuronal dysplasia of the
lymphocyte intestine
proliferation
Decreased Normal Normal Short stature, spondiloepiphyseal dysplasia,
Schimke Immuno-osseous 606622 intrauterine growth retardation; nephropathy;
SMARCAL1 AR
dysplasia bacterial, viral, fungal infections; may present as
SCID; bone marrow failure
T cell lymphopenia, B-cell Hypogammaglobulinemia Short stature; recurrent infections; congenital bone
reduced naïve T deficiency marrow failure, myelodysplasia; immunodeficiency
MYSM1 deficiency MYSM1 AR 612176
cells, low NK cells affecting B-cells and granulocytes; skeletal
anomalies; cataracts; developmental delay
Decreased NK cell Decreased Hypogammaglobulinemia, Recurrent bacterial infections; lymphadenopathy;
function total and variably decreased spondyloepiphyseal dysplasia, extreme intrauterine
MOPD1 Deficiency
RNU4ATAC AR 601428 memory B specific antibodies growth retardation; retinal dystrophy; facial
(Roifman syndrome)
cells dysmorphism; may present with microcephaly; short
stature
Immunoskeletal dysplasia Decreased Normal Decreased or normal Short stature; cervical spinal stenosis,
with neurodevelopmental neurodevelopmental impairment; eosinophilia; may
EXTL3 AR 617425
abnormalities (EXTL3 have early infant mortality
deficiency)

5. Hyper IgE Syndromes (HIES)

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
Distinctive facial features (broad
Normal overall; Th17, T Normal, reduced nasal bridge); bacterial infections
follicular helper, MAIT, memory B cells, (boils, pulmonary abscesses,
NKT cells decreased, BAFF expression Very high IgE, specific pneumatoceles) due to S. aureus,
Tregs may be increased; increased, impaired antibody production secondary pulmonary aspergillosis,
AD-HIES STAT3 AD LOF
impaired responses to responses to STAT3- decreased Pneumocystis jirovecii; eczema,
deficiency (Job STAT3 (dominant 147060
STAT3-activatng cytokines activating cytokines chronic mucocutaneous candidiasis
syndrome) negative)
(CMC); impaired acute phase
response, hyperextensible joints,
osteoporosis and bone fractures,
scoliosis, retained primary teeth;
coronary and cerebral aneurysms
Normal/increased, Normal total and Normal/low serum IgM, G, Atopic dermatitis (eczema), reduced
increased memory Th2 cells; memory B; reduced A. Very high IgE; specific inflammatory responses, recurrent
IL6 receptor deficiency IL6R AR 147880 reduced proportions of cTFh switched memory B antibody production low skin and lung pyogenic bacterial
cells; normal responses to infections, cold abscesses; high
mitogens circulating IL-6 levels

Page 22 of 79
 Normal Th17 cells Reduced switched High IgE, specific antibody Eczema, bacterial infections, boils,
and non-switched production variably eczema, recurrent respiratory tract
memory B cells affected infections (including pneumonia,
bronchiectasis) pulmonary
AR 618523 abscesses; eosinophilia;
pneumatoceles; bone fractures;
retention of primary teeth;
craniosynostosis; scoliosis, impaired
acute phase responses
IL6 signal transducer
Dermatitis/eczema, eosinophilia,
(IL6ST) partial deficiency
recurrent skin infections, pneumonia,
IL6ST
bronchiectasis, pneumatoceles with
Normal, high naive and low severe secondary pulmonary
central memory T cell aspergillosis, connective tissue
frequencies; low proportion of Normal total but low Normal IgM, G, A; hyper- defects (scoliosis, face, joints,
AD 619752
effector memory CD8 T cells; memory IgE fractures, palate, tooth retention).
increased Th2; low frequencies Phenocopies aspects of AR IL6R and
of TFh; low proportions of MAIT IL11R deficiencies (due to
unresponsiveness to these
cytokines), as well as AD STAT3 and
AR ZNF341
Fatal Stuve-Wiedemann-like
syndrome; skeletal dysplasia,
osteoporosis, hyperextensibility, lung
IL6ST complete dysfunction, renal abnormalities,
IL6ST AR 619751 ND death in utero or in neonatal period occurred for most affected individuals)
deficiency thrombocytopenia, dermatitis,
eczema. Defective acute phase
response. Completely unresponsive
to IL-6 family cytokines
Phenocopy of AD-HIES; atopic
Normal, reduced dermatitis/eczema, bacterial skin
Decreased Th17 proportion memory B cells, High IgE and IgG, normal infections and abscesses (S.
and low NK cell counts. impaired responses or subnormal specific aureus), recurrent respiratory
High frequencies of naïve to STAT3-activaitng antibody production infections, lung abscesses and
ZNF341 deficiency 618282
ZNF341 AR CD4+T cells. Low frequencies cytokines pneumatoceles; CMC; mild
AR-HIES
of CD4+ and CD8+ CM T cells. eosinophilia; mild facial
dysmorphism; skeletal/connective
tissue abnormalities (hyperextensible
joints; bone fractures, retention of
primary teeth)
Recurrent respiratory infections,
Increased circulating Treg Normal Moderately increased IgE susceptibility to S. aureus, eczema;
ERBIN deficiency ERBIN AD 606944
hyperextensible joints, scoliosis;
arterial dilatation in some patients
Loeys-Dietz syndrome Recurrent respiratory infections;
TGFBR1 AD 609192 eczema, food allergies; hyper-
(TGFBR deficiency)

Page 23 of 79
 Normal Normal Elevated IgE extensible joints, scoliosis, retention
TGFBR2 610168
of primary teeth; aortic aneurisms.
Normal Normal numbers, High IgE and IgA, Congenital ichthyosis, bamboo hair,
Comel-Netherton Low switched and Antibody variably atopic diathesis; severe atopic
SPINK5 AR 605010
syndrome non-switched B cells decreased manifestations, increased bacterial
infections; failure to thrive
Severe eczema; autoimmunity;
bacterial (s. aureus) and viral
Normal or elevated IgG infections; recurrent skin abscesses,
CD8 and CD4 T cells may Low B and memory and IgA, most with high otitis media, recurrent respiratory
be decreased B cells IgE, eosinophilia tract infection (pneumonia,
bronchiectasis); candidiasis;
eosinophilia; neutropenia; skeletal
PGM3 deficiency PGM3 AR 172100 anomalies/dysplasia (joint
hypermotility and aneurism
formation): short stature,
brachydactyly, dysmorphic facial
features; mild intellectual disability
and cognitive impairment, delayed
CNS myelination in some affected
individuals. Failure to thrive.
Normal number, but High IgE, poor specific Variable atopy, eczema, food
defective T cell activation antibody production; allergies, eosinophilia; cutaneous
CARD11 deficiency
CARD11 AD LOF 617638 and proliferation. Normal to low impaired activation of both viral infections, recurrent respiratory
(heterozygous DN)
skewing toward Th2 NF-B and mTORC1 infections; lymphoma; CID
pathways
Normal numbers. T cells Normal High IgE, normal IgG Early-onset severe allergic
show Th2 skewing diseases, resistant atopic
dermatitis, eosinophilic GI
disease with with reflux,
dysphagia, and eosinophilic
esophagitis, food allergies with
STAT6 GOF STAT6 AD GOF 620532 anaphylaxis, asthma with
interstitial lung disease and
bronchiectasis. Eosinophilia.
Recurrent skin and respiratory
bacterial, viral, and fungal
infections in ~50% . Short stature,
skeletal features.

6. Defects of Vitamin B12 and Folate Metabolism

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features

Page 24 of 79
 Normal Variable Decreased Megaloblastic anaemia, pancytopenia; if
Transcobalamin 2 deficiency TCN2 AR 613441 untreated (B12) for prolonged periods results in
intellectual disability
Variable numbers and Variable Decreased Megaloblastic anaemia, failure to thrive; if
SLC46A1/PCFT deficiency causing
SLC46A1 AR 229050 activation profile untreated for prolonged periods results in
hereditary folate malabsorption
intellectual disability
Low thymic output, Low Decreased/poor antibody Recurrent bacterial infection, Pneumocystis
Methylene-tetrahydrofolate
normal in vitro responses to conjugated jirovecii; megaloblastic anaemia; failure to thrive;
dehydrogenase 1 (MTHFD1) MTHFD1 AR 172460
proliferation polysaccharide antigens neutropenia; seizures, intellectual disability;
deficiency
folate-responsive
mitogen induced-T Slightly Slightly decreased or Recurrent infections, severe pneumonia,
SLC19A1/PCFT deficiency causing SLC19A1
AR NA cell proliferation was low borderline mucositis, megaloblastic folate dependent
hereditary folate malabsorption
significantly reduced anaemia

7. Anhidrotic Ectodermodysplasia with Immunodeficiency (EDA-ID)

Inheritan T cells B cells Ig Associated features
Disease Genetic defect OMIM
ce
Normal or decreased, Normal; Decreased, some with Anhidrotic ectodermal dysplasia (in some);
EDA-ID due to NEMO
TCR activation impaired Low memory and elevated IgA, IgM, poor various infections (bacteria, mycobacteria,
/IKBKG deficiency
IKBKG XL 300248 isotype switched B specific antibody responses, viruses, fungi); colitis; conical teeth, variable
(ectodermal dysplasia,
cells absent antibodies to defects of skin, hair, and teeth; monocyte
immune deficiency)
polysaccharide antigens dysfunction
Normal total T cells, TCR Normal B cell Decreased IgG and IgA, Anhidrotic ectodermal dysplasia.
activation impaired numbers, impaired elevated IgM, poor specific various infections (bacteria, mycobacteria,
EDA-ID due to IKBA GOF BCR activation, low antibody responses, absent viruses, fungi); colitis; variable defects of
NFKBIA AD GOF 164008
mutation memory and isotype antibody to polysaccharide skin, hair, and teeth; T cell and monocyte
switched B cells antigens. dysfunction

EDA-ID due to IKBKB GOF 618204 Decreased T cells, Normal number, Reduced Recurrent bacterial, viral, fungal infections;
IKBKB AD GOF
mutation impaired TCR activation poor function variable ectodermal defects

8. Calcium Channel Defects

Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
ORAI-1 Normal, defective TCR mediated Normal Normal Autoimmunity; EDA; non-progressive myopathy
ORAI1 AR 610277
deficiency activation
STIM1 deficiency STIM1 AR 605921
CRACR2A Mild reduction in T cell numbers Normal Low Later onset, chronic diarrhea, recurrent lower respiratory tract
CRACR2A AR NA
deficiency infections, including pneumonia

Page 25 of 79
 Low T cell numbers, impaired T Low. Low Charcot-Marie Tooth in one patient. CID, ITP, AIHA. Recurrent
cell activation and Trend to infections, enteropathy.
ITPR3 ITPR3 AR NA proliferation. lower
proliferati
ons

9. Other Defects
Disease Genetic defect Inheritance OMIM T cells B cells Ig Associated features
Purine nucleoside Progressive decrease Normal Normal or low Autoimmune haemolytic anaemia;
phosphorylase (PNP) PNP AR 164050 neurological impairment
deficiency
Variable, but sometimes Normal or low Markedly decreased Bacterial (sepsis), fungal, viral infections;
Immunodeficiency with absent or low TRECs at IgG, IgM, IgA multiple intestinal atresias, often with
TTC7A AR 609332
multiple intestinal atresias NBS; may have SCID intrauterine polyhydramnios and early demise
phenotype at birth
TTC37 222470 Variably low Hypogammaglobulin Respiratory infections; IUGR; facial
Tricho-Hepato-Enteric Impaired IFN production numbers of emia, may have low dysmorphic features, wooly hair; early onset
AR 614602
Syndrome (THES) SKIV2L switched memory antibody responses intractable diarrhea, liver cirrhosis; platelet
B cells abnormalities
Normal Normal Decreased IgG, IgA, Hepatic veno-occlusive disease; susceptibility
Hepatic veno-occlusive (decreased memory T (decreased IgM, absent to Pneumocystis jirovecii pneumonia, CMV,
disease with SP110 AR 604457 cells) memory B cells) germinal center and candida; thrombocytopenia;
immunodeficiency (VODI) tissue plasma cells hepatosplenomegaly; cerebrospinal
leukodystrophy
Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth,
BCL11B deficiency BCL11B AD 617237 dysmorphic facies; absent corpus callosum,
neurocognitive deficits
Profound depletion of Defective Decreased Agenesis of the corpus callosum; cataracts;
EPG5 deficiency (Vici CD4+ cells (particularly IgG2) cardiomyopathy; skin hypopigmentation;
EPG5 AR 615068
syndrome) intellectual disability; microcephaly; recurrent
infections, chronic mucocutaneous candidiasis
Normal numbers Normal, Poor antibody Bacterial infections; autoinflammation;
HOIL1 deficiency RBCK1 AR 610924 decreased responses to amylopectinosis
memory B cells polysaccharides
Normal numbers Normal, decreased Bacterial infections; autoinflammation;
HOIP deficiency RNF31 AR 612487 decreased amylopectinosis; lymphangiectasia
memory B cells
Low/variable Low/variable decreased Lymphangiectasia and lymphedema with facial
CCBE1 AR 612753
Hennekam-lymphangiectasia- abnormalities and other dysmorphic features
lymphedema syndrome Low/variable Low/variable decreased Lymphangiectasia and lymphedema with facial
FAT4 AR 612411
abnormalities and other dysmorphic features
Activating de novo mutations Not reported Decreased Hypogammaglobulin Recurrent respiratory and skin infections;
in nuclear factor, erythroid 2- NFE2L2 AD 617744 switched memory emia, decreased growth retardation, developmental delay; white
like (NFE2L2) B cells antibody responses matter cerebral lesions; increased level of

Page 26 of 79
 homocysteine; increased expression of stress
response genes
Modestly decreased, Normal hypergammaglobulin Growth-hormone insensitive dwarfism;
reduced Treg number and emia, increased IgE dysmorphic features; eczema; lymphocytic
AR 245590
function interstitial pneumonitis; prominent
STAT5B deficiency STAT5B autoimmunity
AD Normal Normal Increased IgE Growth-failure; eczema (no immune defects
(dominant 604260 compared to AR STAT5 deficiency)
negative)
Typical facial abnormalities, cleft or high
AD 602113
KMT2D Low IgA and arched palate, skeletal abnormalities, short
Kabuki syndrome
Normal Normal occasionally low IgG stature; intellectual disability; congenital heart
XL (females
defects; recurrent infections (otitis media,
(type 1 and 2) KDM6A may be 300128
pneumonia) in 50% of patients; autoimmunity
affected)
may be present
Normal Decreased Hypogammaglobulin Respiratory infections; short stature;
KMT2A deficiency
switched and non- emia, decreased hypertelorism; hairy elbows; developmental
(Wiedemann-Steiner KMT2A AD 605130
switched memory antibody responses delay, intellectual disability
syndrome)
B cells
Reduced naïve T cells Decreased Low IgM, normal IgG Seizures, cortical blindness, microcephaly
DIAPH1 deficiency
DIAPH1 AR 616632 memory B cells syndrome (SCBMS); recurrent bacterial, viral,
fungal infections; B-lymphoma (3/7)
Normal Reduced; Very low EBV susceptibility, recurrent sinopulmonary &
impaired respiratory infections, Pneumocystis jirovecii,
619437
AIOLOS deficiency IKZF3 AD development warts (HPV), M avium, B cell malignancy.
Haploinsufficiency shows autoimmunity and
allergy.
CD28 deficiency CD28 AR NA Normal Normal Normal Susceptibility to HPV infection only
Low or normal NK cells. Multiple bacterial
Low maybe due to infections. Nephrotic syndrome, adrenal
SGPL1 deficiency SGPL1 AR 617575 Low Low nephrotic insufficiency, ichthyosis/acanthosis,
syndrome dyslipidaemia, mild hypothyroidism,
neurological defects
Low T cell counts in Recurrent infections, lymphoproliferation,
infancy. Total T cell and/or autoimmunity and presence of
counts gradually autoantibodies. Some (6/10) individuals are
increased to reach healthy, some can have small or no visible
normal ranges. Low thymus. Low frequency of MAIT. High
PTCRA deficiency PTCRA AR NA Normal
circulating naive  T proportion of CD4-CD8- DN αβ T cells
cell counts, normal among naive T cells
memory  T cell counts
and high naïve  T cell
counts, low TRECs
Hypoplastic anaemia, monocytopenia, DC-
FLT3L deficiency FLT3LG AR NA Normal Decreased Increased penia, low/absence of dermal DCs. NK cells
normal. Recurrent and persistent viral

Page 27 of 79
 infections, with severe warts, bacterial
(pneumonia, otitis media, pharyngitis, and
cellulitis) and fungal infections. Recurrent
diarrhea from early infancy and failure to
thrive

EDA: ectodermal dysplasia anhydrotic ; HSV: herpes simplex virus, VZV: varicella zoster virus, BCG : Bacillus Calmette-Guerin; NBS: newborn screen, TREC: T-cell receptor excision circle (biomarker for low T
cells used in NBS); IUGR: interuterine growth retardation; CID: combine immune deficiency; ITP: Idiopathic thrombocytopenic purpura; AIHA: autoimmune hemolytic anemia

Total number of mutant genes in Table II: 82 two entries for IL6ST, two entries for STAT5B and two for FOXN1 with distinct but partially overlapping phenotypes)

New inborn errors of immunity: 9, Dominant negative (DN) IKZF2, GINS4, STAT6-GOF, SLC19A1, SGPL1, PTCRA, FLT3L, ITPR3, RECQL432-43
Unknown cause of DiGeorge syndrome, unknown cause of CHARGE syndrome, unknown gene(s) within 10p13-14 deletion responsible for phenotype.

Table III: Predominantly Antibody Deficiencies

1. Severe Reduction in All Serum Immunoglobulin Isotypes with Profoundly Decreased or Absent B Cells, Agammaglobulinemia
Disease Genetic defect Inheritance OMIM Ig Associated features
All isotypes decreased in majority of Severe bacterial infections,
BTK deficiency, X-linked
BTK XL 300300 patients; some patients have normal numbers of pro-B cells
agammaglobulinemia (XLA)
detectable immunoglobulins
 heavy chain deficiency IGHM AR 147020
5 deficiency IGLL1 AR 146770
Severe bacterial infections,
Ig deficiency CD79A AR 112205 normal numbers of pro-B cells
Ig deficiency CD79B AR 147245
BLNK deficiency BLNK AR 604515
p110 deficiency PIK3CD AR 602839 Severe bacterial infections; autoimmune complications (IBD)
Severe bacterial infections, cytopenias, decreased or absent
p85 deficiency PIK3R1 AR 615214
pro-B cells
TCF3 AD 616941 Recurrent bacterial infections
E47 transcription factor deficiency
AR 619824 All isotypes decreased. Severe, recurrent bacterial infections, failure to thrive
Early onset infections, blistering dermatosis, failure to thrive,
SLC39A7 (ZIP7) deficiency SLC39A7 AR 601416
thrombocytopenia
Hoffman syndrome/TOP2B deficiency TOP2B AD 126431 Recurrent infections, facial dysmorphism, limb anomalies

Page 28 of 79
 Early onset recurrent infections, bronchiectasis, fibrosis,
interstitial pneumoniae; neutropenia (severe or intermittent);
FNIP1 deficiency (6 patients) FNIP1 AR 619705
Crohn disease (one patient); congenital heart defects, muscular
hypotonia; developmental delay
Sinopulmonary infections with encapsulated bacteria, viral
PU1 deficiency SPI1 AD 619707
infections
Early B cell developmental block, B cell strongly decreased,
transitional and naive mature B cells expressed lower CD19
and IgD - natural effector and memory B cells as well as
PAX5 deficiency (n=1) PAX5 AR plasmablasts, were absent in the blood of the patient; a-
/hypo-gammaglobulinemia, recurrent infections, autism
spectrum disorder (ASD) and sensorimotor and cognitive
defects

2. Severe Reduction in at Least 2 Serum Immunoglobulin Isotypes with Normal or Low Number of B Cells, CVID Phenotype
Disease Genetic defect Inheritance OMIM Ig Associated features

NA Clinical phenotypes vary most have recurrent infections, some

Common variable immune deficiency with no
Unknown Variable Low IgG and IgA and/or IgM have polyclonal lymphoproliferation, autoimmune cytopenias
gene defect specified (CVID)
and/or granulomatous disease
Severe bacterial infections, reduced memory B cells and
615513 increased transitional B cells, EBV ± CMV viremia,
PIK3CD GOF AD
(APDS1) lymphadenopathy/splenomegaly, autoimmunity,
Activated p110 syndrome (APDS) lymphoproliferation, lymphoma
Normal/increased IgM, Severe bacterial infections, reduced memory B cells and
616005 reduced IgG and IgA
PIK3R1 AD increased transitional B cells, lymphadenopathy/splenomegaly,
(APDS2)
lymphoproliferation, lymphoma; developmental delay
Normal/Decreased Recurrent infections, Lymphoproliferation, Autoimmunity;
PTEN Deficiency (LOF) PTEN AD 158350
developmental delay
CD19 deficiency CD19 AR 107265 Low IgG and IgA and/or IgM Recurrent infections, may have glomerulonephritis (CD81
mutation abolishes expression of CD19, thereby phenocopying
Low IgG, low or normal IgA CD19 mutations)
CD81 deficiency CD81 AR 186845
and IgM
Low IgG, normal or elevated Recurrent infections
CD20 deficiency MS4A1(CD20) AR 112210
IgM and IgA
Low IgG, impaired anti- Recurrent infections
CD21 deficiency CR2 (CD21) AR 120650
pneumococcal response
Low IgG and IgA and/or IgM Variable clinical expression and penetrance for monoallelic
TACI deficiency# TNFRSF13B AR or AD 604907
variants
BAFF receptor deficiency TNFRSF13C AR 606269 Low IgG and IgM, Variable clinical expression

Page 29 of 79
 Low IgM and A, lack of anti- Pneumonia, bacterial infections, warts, thrombocytopenia,
TWEAK deficiency TNFSF12 AD 602695
pneumococcal antibody neutropenia
B cell deficiency and Congenital sideroblastic anemia, deafness, developmental delay
TRNT1 deficiency TRNT1 AR 612907
hypogammaglobulinemia
Normal or low IgG, IgA, IgM, Recurrent sinopulmonary infections, COPD, EBV proliferation,
NFKB1 deficiency NFKB1 AD 164011 low or normal B cells, low autoimmune cytopenias, alopecia and autoimmune thyroiditis
memory B cells
615577 Low serum IgG, A and M; low Recurrent sinopulmonary infections, alopecia and
NFKB2 deficiency NFKB2 AD
B cell numbers endocrinopathies
AD Low IgG, IgA, IgM, low or Decreased pro-B cells, recurrent sinopulmonary infections;
IKAROS deficiency IKZF1 (haploinsuffici 603023 normal B cells; B cells and Ig increased risk of ALL, autoimmunity, CVID phenotype
ency) levels reduce with age
Hypogammaglobulinemia, Recurrent infections, possible autoimmunity and inflammatory
IRF2BP2 deficiency IRF2BP2 AD 615332
absent IgA disease
Variable immunoglobulin Hepatopathy, leukopenia, low
ATP6AP1 deficiency ATP6AP1 XL 300972
findings copper
ARHGEF1 deficiency ARHGEF1 618459 Hypogammaglobulinemia; Recurrent infections, bronchiectasis
AR
lack of antibody
300310 IgM, IgG deficiency; loss of Severe bacterial infections
SH3KBP1 (CIN85) deficiency SH3KBP1 XL
antibody
609213 Hypogammaglobulinemia Severe recurrent respiratory tract infections
SEC61A1 deficiency SEC61A1 AD
Low IgG, IgA, IgM, low or Recurrent sinopulmonary infections, selective IgA deficiency;
602049 normal B cells; reduced Ab poststreptococcal glomerulonephritis; urticaria
RAC2 deficiency RAC2 AR
responses following
vaccination
Low IgG, IgA, IgM, increased
Mannosyl-oligosaccharide glucosidase Bacterial and viral infections; severe neurologic disease; also
MOGS AR 601336 B cells; poor Ab responses
deficiency known as congenital disorder of glycosylation type IIb (CDG-IIb)
following vaccination
PIK3CG Reduced memory B cells, Recurrent infections, Cytopenia /lymphopenia, eosinophilia,
PIK3CG deficiency AR 619802
hypogammaglobulinemia splenomegaly, lymphadenopathy, HLH-like
Reduced memory B cells, Recurrent respiratory infections, possible chronic viral infection
BOB1 deficiency POU2AF1 AR NA
agammaglobulinemia of CNS with progressive tetraparesia
impaired B cell metabolism
(decreased mitochondrial Severe developmental delay,
numbers and activity). B sensorioneural deafness, acute disseminated
KARS1 deficiency KARS1 AR 619147 cell lymphopenia, encephalomyelitis,
hypogammaglobulinemia, central and peripheral nervous system impairment, heart
impaired vaccine and liver disease. Recurrent/severe infections
responses

3. Severe Reduction in Serum IgG and IgA with Normal/Elevated IgM and Normal Numbers of B cells, Hyper IgM

Page 30 of 79
Disease Genetic defect Inheritance OMIM Ig Associated features
IgG and IgA decreased, Bacterial infections, enlarged lymph nodes and germinal centers;
IgM increased; normal autoimmunity
AR 605258
memory B cells but lacking
somatic hypermutation
AID deficiency
AICDA IgG absent or decreased, Bacterial infections, enlarged lymph nodes and germinal centers.
IgA undetected, IgM Variants uniquely localise to the nuclear export signal.
AD NA increased; normal memory
B cells with intact somatic
hypermutation
IgG and IgA decreased, Enlarged lymph nodes and germinal centers
UNG deficiency UNG AR 191525
IgM increased
IgG and IgA decreased, Severe bacterial infections
INO80 deficiency INO80 AR 610169
IgM increased
Variable IgG, defects,
increased IgM in some,
normal B cells, low
MSH6 deficiency MSH6 AR 600678 switched memory B cells, Family or personal history of cancer
Ig class switch
recombination and somatic
hypermutation defects
Reduced memory B cells, CVID, autoimmune cytopenias, recurrent infections, hyperplastic
Ig class switch germinal centers
CTNNBL1 recombination and somatic
CTNNBL1 deficiency AR NA
hypermutation defects,
progressive
hypogammaglobulinemia
Normal total B cell counts, CVID, chronic but mild infections, alopecia areata
Reduced memory B cells,
APRIL deficiency TNFSF13 AR NA hypogammaglobulinemia

4. Isotype, Light Chain, or Functional Deficiencies with Generally Normal Numbers of B Cells
Disease Genetic defect Inheritance OMIM Ig Associated features
Mutation or One or more IgG and/or IgA
chromosomal subclasses as well as IgE may be May be asymptomatic
Ig heavy chain mutations and deletions AR absent
deletion at
14q32

Page 31 of 79
 147200 All immunoglobulins have lambda Asymptomatic
Kappa chain deficiency IGKC AR
light chain
Usually asymptomatic, a minority may have poor antibody
Isolated IgG subclass deficiency Unknown ND Reduction in one or more IgG response to specific antigens and recurrent viral/bacterial
subclass infections
Unknown Reduced IgA with decrease in one Recurrent bacterial infections
IgG subclass deficiency with IgA deficiency ND
or more IgG subclass May be asymptomatic
Unknown Absent IgA with other isotypes May be asymptomatic Bacterial infections, autoimmunity
Selective IgA deficiency ND normal, normal subclasses and mildly increased
specific antibodies
Specific antibody deficiency with normal Ig Unknown Normal Reduced ability to produce antibodies to specific antigens
ND
levels and normal B cells
Transient hypogammaglobulinemia of Unknown Normal ability to produce antibodies to vaccine antigens,
ND
infancy IgG and IgA decreased usually not associated with significant infections
616452 polyclonal B cell lymphocytosis Splenomegaly, lymphadenopathy, poor vaccine response
CARD11 GOF CARD11 AD GOF due to constitutive NF-κB
activation
Selective IgM deficiency Unknown ND Absent serum IgM Pneumococcal / bacterial

EBV, Epstein Barr virus; COPD, chronic obstructive pulmonary disease; ND, not determined

Common Variable Immunodeficiency Disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known
genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Identification of causal variants can assist in defining treatment. In addition to monogenic causes on this table, a small
minority of patients with XLP (Table IV), WHIM syndrome (Table VI), ICF (Table II), VODI (Table II), thymoma with immunodeficiency (Good syndrome) or myelodysplasia are first seen by an immunologist
because of recurrent infections, hypogammaglobulinemia and normal or reduced numbers of B cells.

# heterozygous variants in TNFRSF13B have been detected in healthy individuals, thus such variants are likely to be disease-modifying rather than disease-causing

Total number of mutant genes in Table III: 47

New inborn errors of immunity: 2; PAX5, KARS144,45

Page 32 of 79
Table IV: Diseases of Immune Dysregulation

1. Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes)

Circulating T Circulating
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
Cells B cells
Decreased to absent NK Fever, HSM,
Increased Normal and CTL activities hemophagocytic
Perforin deficiency (FHL2) PRF1 AR 170280
activated T cells cytotoxicity lymphohistiocytosis (HLH),
cytopenias
UNC13D / Munc13-4 deficiency (FHL3) UNC13D AR 608897 Decreased to absent NK Fever, HSM, HLH,
Increased Normal and CTL activities cytopenias
Syntaxin 11 deficiency (FHL4) STX11 AR 605014
activated T cells (cytotoxicity and/or
STXBP2 / Munc18-2 deficiency (FHL5) STXBP2 AR or AD 601717 degranulation)
Failure to kill autologous EBV-driven
610884 Increased Normal EBV transformed B lymphoproliferative disease
FAAP24 deficiency FAAP24 AR
activated T cells cells. Normal NK cell
function
Normal Normal Hyper-inflammatory Lysinuric protein intolerance,
response of bleeding tendency, alveolar
SLC7A7 deficiency SLC7A7 AR 222700
macrophages proteinosis
Normal NK cell function
Normal Slightly Impaired CTL and NK HLH (hemophagocytosis,
reduced cell cytotoxicity hepatosplenomegaly, fever,
RHOG deficiency RHOG AR NA cytopenias, low hemoglobin,
hyper-triglyceridemia,
elevated ferritin, sCD25)
NA NA Aberrant activation of Increased susceptibility to
the canonical NLRP1 infection (herpes,
inflammasome and IL- bronchitis, otitis media)
1β signalling. pancytopenia (petechiae),
620331 Hyperinflammation recurrent fever, skin
DPP9 deficiency DPP9 AR
with increased levels pigmentation
of IL-1b and IL-18 due abnormalities. Poor growth
to loss of NLRP1 (short stature, failure to
repression. Normal NK thrive)
cell function

Page 33 of 79
 2. FHL Syndromes with Hypopigmentation
Circulating T Circulating B
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
Cells cells
Partial albinism,
recurrent infections,
Increased Normal Decreased NK and fever, HSM, HLH, giant
activated T CTL activities lysosomes,
Chediak-Higashi syndrome LYST AR 606897 cells (cytotoxicity and/or neutropenia,
degranulation) cytopenias, bleeding
tendency, progressive
neurological
dysfunction
Decreased NK and
Normal Normal CTL activities Partial albinism, fever,
Griscelli syndrome, type 2 RAB27A AR 603868
(cytotoxicity and/or HSM, HLH, cytopenias
degranulation)
Decreased NK and Partial albinism,
CTL activities recurrent infections,
Hermansky-Pudlak syndrome, type 2 AP3B1 AR 603401 Normal Normal (cytotoxicity and/or pulmonary fibrosis,
degranulation) increased bleeding,
neutropenia, HLH
Decreased NK and Oculocutaneous
CTL activities albinism, severe
Normal Normal (cytotoxicity and/or neutropenia, recurrent
Hermansky-Pudlak syndrome, type 10 AP3D1 AR 617050 degranulation) infections, seizures,
hearing loss and
neurodevelopmental
delay
Mild reduction Not done Autoinflammasome Recurrent abdominal
activation/ IFN pain, aseptic fever,
gene expression, systemic inflammation;
altered chromatin abscesses, ulceration,
CEBPE multimorphic CEBPE AR GOF 260570 occupancy of infections; mild
mutant CEBPE, bleeding diathesis
and transcriptional
changes

3. Regulatory T Cell Defects

Circulating T Circulating
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
Cells B cells
Normal Normal Lack of (and/or impaired Autoimmune enteropathy, early
function of) CD4+ CD25+ onset diabetes, thyroiditis
IPEX, immune dysregulation,
FOXP3 XL 300292 FOXP3+ regulatory T hemolytic anemia,
polyendocrinopathy, enteropathy X-linked
cells (Tregs) thrombocytopenia, eczema,
elevated IgE and IgA
Normal to Normal No CD4+C25+ cells with Lymphoproliferation,
CD25 deficiency IL2RA AR 147730 decreased impaired function of autoimmunity, impaired T cell
Tregs cells proliferation in vitro

Page 34 of 79
 Increased Increased Diminished IL2R Lymphoproliferation,
memory CD8 memory B expression, lymphadenopathy,
T cells, cells dysregulated signaling in hepatosplenomegaly,
decreased response to IL-2/IL-15; autoimmune hemolytic anemia,
CD122 deficiency IL2RB AR 618495
Tregs increased immature NK dermatitis, enteropathy,
cells hypergammaglobulinemia,
recurrent viral (EBV, CMV)
infections
Decreased Decreased Impaired function of Autoimmune cytopenias,
Tregs. enteropathy, interstitial lung
CTLA4 haploinsufficiency (ALPS-V) CTLA4 AD 123890 disease, extra-lymphoid
lymphocytic infiltration, recurrent
infections
Normal or Low or Reduced IgG and IgA in Recurrent infections,
decreased normal most inflammatory bowel disease,
LRBA deficiency LRBA AR 606453 CD4 numbers numbers of autoimmunity
T cell B cells
dysregulation
Mild CD4 and Low or Impaired Treg function Enteropathy,
CD8 normal hepatosplenomegaly,
DEF6 deficiency DEF6 AR 610094
lymphopenia numbers of cardiomyopathy, recurrent
B cells infections
Low CTLA-4 grey platelet syndrome
expression (macrothrombocytopenia, α-
in effector T granule deficient platelets,
cells, normal bleeding disorders)
NBEAL2 deficiency NBEAL2 AR 139090
regulatory T splenomegaly and progression
cells to myelofibrosis. Autoimmune
lymphoproliferative syndrome,
EBV reactivation, MAS
Enhanced STAT3
signaling, leading to
increased Th17 cell Lymphoproliferation, solid organ
Decreased Decreased differentiation, autoimmunity, recurrent
STAT3 GOF STAT3 AD GOF 102582
lymphoproliferation and infections
autoimmunity.
Decreased Tregs and
impaired function
Progressive T Impaired Haploinsufficiency for a Lymphocytic colitis,
605394 cell memory B critical lineage sinopulmonary infections
BACH2 deficiency BACH2 AD
lymphopenia cell specification
development transcription factor
Normal Normal Intracellular Dermatosis characterized by
accumulation of IgG, congenital blistering, skin
FERMT1 deficiency FERMT1 AR 173650
IgM, IgA, and C3 in atrophy, photosensitivity, skin
fragility, and scaling

Page 35 of 79
 colloid bodies under the
basement membrane
Normal Normal/mild Increased binding of Multiple autoimmune features
decrease mutant IKAROS to (diabetes, colitis, thyroiditis),
DNA/target genes allergy, lymphoproliferation,
IKAROS GOF IKZF1 AD GOF NA
plasma cell expansion (IgG4+),
Evans Syndrome, recurrent
infections

Page 36 of 79
 4. Autoimmunity with or without Lymphoproliferation
Genetic Circulating B
Disease Inheritance OMIM Circulating T Cells Functional defect Associated Features
defect cells
Autoimmunity: hypoparathyroidism,
hypothyroidism, adrenal
AIRE serves as check- insufficiency, diabetes, gonadal
APECED (APS-1), autoimmune Normal Normal point in the thymus for dysfunction and other endocrine
240300
polyendocrinopathy with candidiasis AIRE AR or AD negative selection of abnormalities; dental enamel
and ectodermal dystrophy autoreactive T cells and hypoplasia, alopecia areata
for generation of Tregs enteropathy, pernicious anemia;
chronic mucocutaneous
candidiasis
Itch deficiency may Early-onset chronic lung disease
cause immune (interstitial pneumonitis),
dysregulation by autoimmunity (thyroiditis, type I
Not assessed Not assessed affecting both anergy diabetes, chronic
ITCH deficiency ITCH AR 606409
induction in auto- diarrhea/enteropathy, and
reactive effector T cells hepatitis), failure to thrive,
and generation of Tregs developmental delay, dysmorphic
facial features
TPP2 deficiency results Variable lymphoproliferation,
Decreased Decreased in premature severe autoimmune cytopenias,
Tripeptidyl-Peptidase II Deficiency TPP2 AR 190470 immunosenescence hypergammaglobulinemia,
and immune recurrent infections
dysregulation
HSM, eosinophilia, eosinophilic
147795
JAK1 GOF JAK1 AD GOF Not assessed Not assessed Hyperactive JAK1 enteritis, thyroid disease, poor
growth, viral infections
Normal Normal Peptidase D Autoantibodies common, chronic
Prolidase deficiency PEPD AR 613230
skin ulcers, eczema, infections
Decreased Reduced pSTAT1,  type I/II Early onset severe multisystemic
switched memory IFN signature autoimmunity, neutropenia,
B cells lymphopenia, ITP, AIHA, SLE, GN,
SOCS1 haploinsufficiency SOCS1 AD 619375 hepatosplenomegaly, psoriasis,
arthritis, thyroiditis, hepatitis;
recurrent bacterial infections.
Incomplete penetrance
Mostly intact Normal Lack of PD-1 on patient Tuberculosis, autoimmunity (T1D,
expansion of PBMCs, reduced IFN hypothyroidism, JIA), fatal
CD4−CD8− double- production in response pulmonary autoimmunity,
PD-1 deficiency PDCD1 AR NA
negative (DN) αβ cells to mycobacterial stimuli hepatosplenomegaly. Decreased
proportions of CD56bright NK,
Vδ2+ γδ T, and MAIT cells;
Normal, higher CD38 impaired IFN- Reduced, not absent Neonatal onset autoimmunity
and HLA-DR exprssion by PD-L1 expression, including T1 diabetes. Reduced
expression on PD-L1 on patient PBMC proportions of Vδ2+ γδ T and NK
PD-L1 deficiency CD274 AR CD4+ and CD8+ αβ T deficiency lymphocytes, MAIT
lymphocytes leukocytes.
Memory B cells
and antibody

Page 37 of 79
 responses can
be impaired.
Enhanced TLR7 Childhood onset SLE with
signalling drives multiple autoantibodies (ANA,
aberrant survival of B dsDNA, U1RNP, etc.),
cell receptor-activated hypocomplementemia, malar
TLR7 monogenic lupus TLR7 AD GOF 301080 Normal Normal, B cells. rash, autoimmune cytopenia,
increased IgD- arthralgias, and
CD27- B cells, glomerulonephritis. One patient
age-associated with optic neuritis, and
B cells (ABCs) transverse myelitis.
Reduction of Increased Disrupts TLR Early onset SLE or Chillblain
CD4+ Tcells and hyperreactive trafficking resulting in lupus with refractory
expansion of CD8+ T CD27highCD38high TLR-7 autoimmune thrombocytopenia,
cells plasmablasts hyperactivation, autoimmune anemia, and
increased aberrant recognition erythematous rash,
CD27−IgD− B of self-nucleic acids hepatosplenomegaly,
UNC93B1 monogenic Lupus UNC93B1 AD GOF NA
cells and increased type I glomerulonephritis, arthritis, and
IFN signalling panniculitis. + Autoantibodies.
Transient leukocytosis
(neutrophilia and monocytosis)
& lymphocytopenia. High levels
of lupus-associated cytokines
Low total CD3+ and Normal CD19+; Increased alternative Lymphadenopathy and
CD4+ T cells with with low class- NF-kB signalling in B splenomegaly. B cell
decreased naïve and switched cells. lymphoproliferation. Recurrent
increased central memory B cells sinopulmonary infections with
memory B-cell poor polysaccharide responses
populations. lymphoproliferat and bronchiectasis.
Decreases ion. High IgG, immune dysregulation
proportions of naïve normal to high syndrome
AD- CD8+ T cells. IgM. with autoimmunity and systemic
TRAF3 haploinsufficiency TRAF3 Haploinsuf 614849 Increased Treg and inflammation: Sjogren syndrome
ficiency TFH cells. with positive autoantibodies,
vasculitis, glomerulonephritis,
autoimmune thyroid disease
and systemic juvenile arthritis.
Enteropathy. Multiple
autoantibodies.
Atopic disease, dermatitis,
allergies with high IgE in one
patient.
Normal counts, Normal Resistance to Treg Autoimmune
hyperproliferative suppression and polyendocrinopathy (Thyroid
CBLB deficiency CBLB AR 620430
increased B cell and Type-I DM), autoimmune
signaling cytopenias (AIHA, ITP), vitiligo,

Page 38 of 79
 fevers, and polyserositis.
Multiple autoantibodies.
Normal Normal Exacerbated NFB Cytopenias (AIHA, ITP). Multiple
and type II interferon autoantibodies.
pathway in patient T Lymphadenopathies. May have
PLCG1 GOF disease PLCG1 AD 620514 cells. Hyperactivated low NK cells.
NF-kB and type I
interferon pathway in
monocytes.
NA NA Increased Hepatosplenomegaly or
phosphorylation of splenomegaly with
JAK2, STAT5, and thrombocytosis, neutrophilia,
STAT3. and bone marrow showing
605093
SH2B3 deficiency SH2B3 AR myeloid and megakaryocytic
hyperplasia. Multiorgan
autoimmunity: autoimmune
hepatitis, thyroiditis, Type-I DM,
and alopecia areata.
Immune dysregulation with
immunodeficiency coupled with
Actinopathy. hyperinflammation,
Normal number, DNT Hyperinflammation and lymphoproliferation, and
Increased b cells
NCKAP1L deficiency can be high, Central cytokine overproduction autoimmunity.
NCKAP1L AR 618982 with increased
memory and TEMRA (Th1),  T cell Recurrent infections,
naïve B cell
can be increased. proliferation, bronchiectasis.
proportion.
cytoskeletal defects Hepatosplenomegaly. atopy. HLH
in one patient. Anti dsDNA Abs,
fever, FTT
Low-Normal CD4+ T Recurrent and severe infections,
cell counts, low severe early-onset
recent thymic increased B cell Actinopathy, autoimmunity, inflammation, and
emigrant CD4+ T counts, high Normal/high IgG, IgA, dysmorphisms. Increased NKT
ARPC5 deficiency ARPC5 AR 620565
cell counts, low frequency of and IgM (Ig3 elevated cells, neutrophiila
naive CD8+ T cells, age-associated in 1 pt)
excess of memory
and T EMRA cells
Joint contractures,
osteochondromas, B cell
Normal counts
Calcium-calcineurin lymphoma. No recurrent
increased naïve,
Normal with signals drive cell infections or autoimmunity
transitional,
NFAT1 deficiency NFATC2 AR 620232 increased activation, although there was increased IL-
decreased
exhaustion markers proliferation, and 6 in patient chondrocytes.
switched
survival. EBV driven lymphoproliferation,
memory B cells
hypogamglobulinemia without
osteochondromas may occur.
Impaired autophagy in Systemic juvenile arthritis or
LACC1 deficiency LACC1 AR 618795 NA NA
macrophages polyarticular juvenile arthritis

Page 39 of 79
 Familial autoimmunity including
Defect of IRE1 over SLE, Sjögren syndrome
XBP1 splicing idiopathic thrombocytopenic
IRE1α deficiency ERN1 AD NA Normal Normal resulting in purpura, Hashimoto thyroiditis
breakdown of B cell and limited cutaneous sclerosis.
tolerance Positive ANA, DNA SSA SSB
auto antibodies
Lymphadenopathy and
Transient
splenomegaly. Vasculitis of
lymphopenia,
Normal B cells. CNS, skin, and lungs with
Decreased naïve T
Elevated IgM pulmonary hypertension.
cells with high Tem
and 2 Reduced NK cell Recurrent infections
GIMAP6 Deficiency GIMAP6 AR 616960 and TEMRA CD4+
microglobulin, cytotoxicity (pneumonia) with
cells. Reduced T cell
reduced IgA an bronchiectasis.
proliferation and
IgG levels. Antiphospholipid and
activation and
anticardiolipin autoantibodies.
defective autophagy
Autoimmune hemolytic anemia.

5. Immune Dysregulation with Colitis

Circulating Circulating
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
T Cells B cells
Normal Normal No functional IL-10 Inflammatory bowel disease
IL-10 deficiency IL10 AR 124092 secretion (IBD) Folliculitis, recurrent
respiratory diseases, arthritis,
Normal Normal Leukocytes unresponsive
IL10RA AR 146933
to IL-10 IBD, Folliculitis, recurrent
IL-10R deficiency Normal Normal Leukocytes unresponsive respiratory diseases, arthritis,
IL10RB AR 123889 to IL-10, and IL-22, IL-26, lymphoma
IL-28A, IL-28B and IL-29
Normal Normal Decreased memory B IBD, recurrent sinopulmonary
NFAT5 haploinsufficiency NFAT5 AD 604708
cells and plasmablasts infections
Normal Normal Decreased T cell IBD, immunodeficiency,
proliferation in response recurrent viral infections,
TGFB1 deficiency TGFB1 AR 618213
to anti-CD3 microcephaly, and
encephalopathy
Reduced Normal/ Reduced activation of Recurrent infections, early-onset
618108 Reduced MAPK, NF-kB pathways IBD, progressive polyarthritis
RIPK1 RIPK1 AR
to

Normal Normal Hyper inflammatory Early onset IBD/mucosal

macrophages autoinflammation, fevers, ulcers,
301074
ELF4 deficiency ELF4 XL Responded to IL-1, TNF or IL-
12p40 blockade

Page 40 of 79
 Normal Decreased Abnormal actin Severe early-onset
switched cytoskeleton autoimmunity affecting
memory B remodelling due to various organs, GI (IBD), skin,
cells and impaired CDC42 activity lung, joints, etc. Some with
MZ-like B and STAT5 activation, SLE or JIA diagnosis.
DOCK11 XL 301109
cells Treg defect. Susceptibility to infections
with hyperinflammatory
DOCK11 deficiency response. Normocytic
anemia, variable
thrombocytopenia.
Normal Normal Failure to generate Recurrent sinopulmonary
mature and active infections with
ADAM17 preventing pneumatoceles, eczema,
iRHOM deficiency RHBDF2 AR
TNF cleavage. Impaired hepatosplenomegaly, skin
TNF secretion in T cells abscesses, High IgE.
Low IL-18 Haemorrhagic colitis

6. Autoimmune Lymphoproliferative Syndrome (ALPS, Canale Smith syndrome)

Circulating Circulating
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
T Cells B cells
Increased Normal, Apoptosis defect FAS Splenomegaly, adenopathies,
AD
TCR /+ low memory mediated autoimmune cytopenias, increased
CD4-CD8- B cells lymphoma risk, IgG and A normal
ALPS-FAS FAS/TNFRSF6 134637
double or increased, elevated serum
AR FasL, IL-10, vitamin B12
negative
(DN) T cells
Increased Normal Apoptosis defect Splenomegaly, adenopathies,
ALPS-FASLG FASLG/TNFSF6** AD 134638 DN T cells FASL mediated autoimmune cytopenias, SLE,
soluble FasL is not elevated
Increased Normal Defective lymphocyte Adenopathies, splenomegaly,
ALPS-Caspase10 CASP10 AD 601762
DN T cells apoptosis autoimmunity
Slightly Normal Defective lymphocyte Adenopathies, splenomegaly,
ALPS-Caspase 8 CASP8 AR 601763 increased apoptosis and bacterial and viral infections,
DN T cells activation hypogammaglobulinemia
Increased Normal Defective lymphocyte Functional hyposplenism, bacterial
DN T cells apoptosis and viral infections, recurrent
FADD deficiency FADD AR 602457
episodes of encephalopathy and
liver dysfunction

Page 41 of 79
 7. Susceptibility to EBV and Lymphoproliferative Conditions
Circulating Circulating
Disease Genetic defect Inheritance OMIM Functional defect Associated Features
T Cells B cells
Clinical and immunologic features
Normal or triggered by EBV infection: HLH,
Reduced
Increased Reduced NK cell and CTL Lymphoproliferation, Aplastic
SAP deficiency (XLP1) SH2D1A XL 300490 Memory B
activated T cytotoxic activity anaemia, Lymphoma.
cells
cells Hypogammaglobulinemia,
Absent iNKT cells
Normal or
Increased T cells
Increased Normal or EBV infection, Splenomegaly,
susceptibility to apoptosis
activated T reduced lymphoproliferation
XIAP deficiency (XLP2) XIAP XL 300079 to CD95 and enhanced
cells; Memory B HLH, Colitis, IBD, hepatitis
activation-induced cell
low/normal cells Low iNKT cells
death (AICD)
iNK T cells
Normal No memory Hypogammaglobulinemia; Features triggered by EBV
CD27 deficiency CD27 AR 615122 B cells poor Ab responses to infection, HLH, aplastic anemia,
some vaccines/infections low iNKT cells, B-lymphoma
Normal Decreased Hypogammaglobulinemia; EBV susceptibility, Hodgkin
number, low memory B poor Ab responses to lymphoma; autoimmunity in some
CD70 deficiency CD70 AR 602840 Treg, poor cells some vaccines/infections patients
activation
and function
Normal to Decreased Normal/high IgG Recurrent/chronic bacterial and
low, but memory B poor proliferation to viral infections (EBV, VZV), EBV
CTPS1 deficiency CTPS1 AR 615897 reduced cells antigen lymphoproliferation, B-cell non-
activation, Hodgkin lymphoma
proliferation
Low IgG, low IgA, poor EBV lymphoproliferation, B-cell
responses to T cell- lymphoma, chronic active EBV
Normal Normal dependent and T cell infection
CD137 deficiency (41BB) TNFRSF9 AR 602250 independent antigens,
decreased T cell
proliferation,IFN
secretion, cytotoxicity
Normal Normal CD137L was not up- Disseminated EBV in B and
counts, ↓ regulated on activated CD8+ T cells, smooth muscle
EBV monocytes and tumors
specific T dendritic cells, EBV-
620282 cell effector infected B cells. B cells
TNFSF9 (CD137L) deficiency (41BBL) TNFSF9 AR
responses failed to trigger the
expansion of EBV
specific
T cells, resulting in ↓ T
cell effector responses
Poor Poor Normal IgM, IgG, Recurrent pneumonia,
activation, activation, increased IgA herpesvirus infections, EBV
proliferation, proliferation, associated lymphoma.
RASGRP1 deficiency RASGRP1 AR 603962
motility. motility Decreased NK cell function
Reduced
naïve T cells
Normal Normal B Normal to low, poor T Recurrent bacterial, fungal, and
number, high cell dependent antibody mycobacterial infections, viral
CD4, numbers, response warts, molluscum and EBV
RLTPR deficiency CARMIL2 AR 610859
increased reduced lymphoproliferative and other
naïve CD4+ memory B malignancy, atopy
and CD8+, cells

Page 42 of 79
 low Treg and
MAIT, poor
CD28-
induced
function
Low CD4 Normal but Progressive EBV infection, lymphoma, viral
Low recent decreased hypogammaglobulinemia infections, respiratory and GI
thymic memory B Reduced NK cell and CTL infections
emigrant cells cytotoxic activity due to Glycosylation defects
cells, impaired expression of
inverted NKG2D
X-linked magnesium EBV and neoplasia
MAGT1 XL 300853 CD4/CD8
(XMEN)
ratio,
reduced
MAIT cells,
poor
proliferation
to CD3
Recurrent infections, EBV chronic
Low memory infection, lymphoproliferation,
615559
PRKCD deficiency PRKCD AR Normal B cells, high Apoptotic defect in B cells SLE-like autoimmunity (nephrotic
CD5 B cells and antiphospholipid syndromes),
low IgG
ALPS-like, recurrent viral
infections, EBV viremia,
Increased Low memory DNA hypermethylation, lymphadenopathy,
TET2 deficiency TET2 AR 619126
CD4-CD8- T B cells defective FAS-mediated hepatosplenomegaly,
cells apoptosis autoimmunity, B-lymphoma, FTT,
developmental delay
Phosphorylation of Acute and severe primary EBV
STAT1 and STAT3 by infection with a favourable
Normal Normal IL-27 is abolished in T outcome
IL-27RA deficiency IL27RA AR cells, impaired
expansion of potent
anti-EBV effector
cytotoxic CD8+ T cells

FHL: Familial hemophagocytic lymphohistiocytosis, , Hemophagocytic lymphohistiocytosis, HLH, Hepatosplenomegaly, HSM, DN, double-negative, SLE, systemic lupus erythematous, IBD, Inflammatory bowel
disease

Total number of defects in Table IV: 71

New inborn errors of immunity: 18 CD274 (PDL1), TLR7 GOF, UNC93B1 GOF, TRAF3, CBLB, PLCG1, SH2B3, ARPC5, NFATC2, DOCK11, RHBDF2, LACC1, ERN1, NBEAL2, IL27RA, TNFSF9, DPP9,
GIMAP6 22,24,46-66

Page 43 of 79
Table V: Congenital defects of phagocyte number or function

1. Congenital Neutropenias
Inheritanc
Disease Genetic defect OMIM Affected cells Affected function Associated features
e
Susceptibility to MDS/leukemia
Elastase deficiency (Severe congenital
ELANE AD 130130 N Myeloid differentiation Severe congenital neutropenia or
neutropenia [SCN] 1)
cyclic neutropenia
GFI 1 deficiency (SCN2) GFI1 AD 600871 N Myeloid differentiation B/T lymphopenia
N Myeloid differentiation Cognitive and neurological defects in
patients with defects in both HAX1
HAX1 deficiency (Kostmann Disease) (SCN3) HAX1 AR 605998
isoforms, susceptibility to
MDS/leukemia
N Myeloid differentiation, Structural heart defects, urogenital
chemotaxis, abnormalities, inner ear deafness, and
G6PC3 deficiency (SCN4) G6PC3 AR 611045
O2- production venous angiectasias of trunks and
limbs
N Myeloid differentiation, Extramedullary hematopoiesis, bone
VPS45 deficiency (SCN5) VPS45 AR 610035
migration marrow fibrosis, nephromegaly
N+M Myeloid differentiation, Fasting hypoglycemia, lactic acidosis,
Glycogen storage disease type 1b SLC37A4/G6PT1 AR 602671 chemotaxis, hyperlipidemia, hepatomegaly
O2- production
N Differentiation, mitosis. Neutropenia, myeloid maturation
Results from GOF arrest, monocytopenia, variable
X-linked neutropenia/myelodysplasia WAS XL GOF 300299
mutations in GTPase lymphoid anomalies
binding domain of WASp
N+M Endosomal biogenesis Neutropenia
Hypogammaglobulinemia ¯CD8
P14/LAMTOR2 deficiency LAMTOR2 AR 610389
cytotoxicity, partial albinism, growth
failure
N+L Mitochondrial function Cardiomyopathy, myopathy, growth
Barth Syndrome
TAZ XL 300394 Mel retardation, neutropenia
(3-Methylglutaconic aciduria type II)
N Myeloid differentiation Dysmorphism, mental retardation,
Cohen syndrome VPS13B AR 607817
obesity, deafness, neutropenia
Clericuzio syndrome (Poikiloderma with N Myeloid differentiation Retinopathy, developmental delay,
USB1 AR 613276
neutropenia) facial dysmorphisms, poikiloderma
JAGN1 deficiency JAGN1 AR 616012 N Myeloid differentiation Myeloid maturation arrest, osteopenia
N Myeloid differentiation Neurocognitive developmental
Mitochondrial protein aberrations, microcephaly,
3-Methylglutaconic aciduria CLPB AD/AR 616254
hypoglycemia, hypotonia, ataxia,
seizures, cataracts, IUGR
N Stress granulopoiesis
G-CSF receptor deficiency CSF3R AR 138971
disturbed

Page 44 of 79
 N Chromatin remodeling, Neutropenia, developmental
SMARCD2 deficiency SMARCD2 AR 601736 Myeloid differentiation and aberrations, bones, hematopoietic
neutrophil functional defect stem cells, myelodysplasia
N Terminal maturation and Neutropenia, Neutrophils with bilobed
CEBPE deficiency CEBPE AR 245480 global dysfunction nuclei, poor chemotaxis
N Pancytopenia, exocrine pancreatic
SBDS AR 607444
insufficiency, chondrodysplasia
Shwachman-Diamond Syndrome DNAJC21 AR 617052 N + HSC Neutrophil maturation, Pancytopenia, exocrine pancreatic
N + HSC chemotaxis, ribosomal insufficiency
EFL1 AR 617941 biogenesis
N Unfolded protein response Hypoglycemia, inflammatory
HYOU1 deficiency HYOU1 AR 601746
complications
N Protein translocation to Neutropenia, exocrine pancreatic
604857 ER, myeloid differentiation insufficiency
SRP54 deficiency SRP54 AD
and neutrophil functional
defect
Reduced expression of Profound neutropenia, myelokathexis,
N CXCR2 on patient cells, recurrent gingivitis, oral ulcers,
CXCR2 deficiency CXCR2 AR 619407
impaired responses to hypergammaglobulinemia
CXCL8
N Disturbed cell cycle Neurocognitive developmental
DBF4 deficiency DBF4 AR NA
aberrations
N Alterations in neutrophil Exocrine pancreatic insufficiency,
SRP19
granulocyte development growth insufficiency, recurrent
SRP19 / SRPRA deficiency AR NA with reduction in pulmonary infections with
SRPRA electron dense granules bronchiectasis, congenital
neutropenia

2. Defects of Motility
Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
N+M+ Adherence, Chemotaxis, Delayed cord separation, skin ulcers,
Leukocyte adhesion deficiency type 1 (LAD1) ITGB2 AR 600065 L + NK Endocytosis, T/NK periodontitis, leukocytosis
cytotoxicity
N+M Rolling, chemotaxis Mild LAD type 1 features with hh-blood group,
Leukocyte adhesion deficiency type 2 (LAD2) SLC35C1 AR 605881
growth retardation, developmental delay
N+M+ Adherence, chemotaxis LAD type 1 plus bleeding tendency
Leukocyte adhesion deficiency type 3 (LAD3) FERMT3 AR 607901
L + NK
N Adherence, chemotaxis Poor wound healing, leukocytosis
Rac2 deficiency RAC2 AD LOF 608203
O2 - production
 actin deficiency ACTB AD 102630 N+M Motility Mental retardation, short stature
N Formylpeptide induced Periodontitis only
Localized juvenile periodontitis FPR1 AR 136537
chemotaxis

Page 45 of 79
 N+M Chemotaxis Periodontitis, palmoplantar hyperkeratosis in
Papillon-Lefèvre Syndrome CTSC AR 602365
some patients
604734 N Spreading, survival, Mild neutropenia, poor wound healing, severe
WDR1 deficiency WDR1 AR
chemotaxis stomatitis, neutrophil nuclei herniate
602421 M only Chemotaxis Respiratory infections, pancreatic insufficiency,
Cystic fibrosis CFTR AR
elevated sweat chloride
Neutropenia with combined immune N + M +L + NK Impaired expression of Mild thrombocytopenia
MAP3K9/ MKL1 AR 606078
deficiency due to MKL1 deficiency cytoskeletal genes
M Impaired CCL2-dependent Pulmonary alveolar proteinosis (PAP),
monocyte migration to the progressive polycystic lung disease, and
CCR2 CCR2 AR
lungs and infected tissues recurrent infections, including bacillus
Calmette Guérin (BCG) disease

3.Defects of Respiratory Burst

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
Infections, autoinflammatory phenotype,
IBD
X-linked chronic granulomatous disease
CYBB XL 306400 McLeod phenotype in patients with
(CGD), gp91phox
deletions extending into the contiguous
Kell locus
CYBA 608508
N+M Killing (faulty O2 - production)
CYBC1 618334
Infections, autoinflammatory phenotype
Autosomal recessive CGD NCF1 AR 608512
NCF2 608515
613960
NCF4
G6PD deficiency class I G6PD XL 305900 N Reduced O2− production Infections

4. Other Non-Lymphoid Defects

Affected
Disease Genetic defect Inheritance OMIM Affected function Associated features
cells
XL Alveolar proteinosis
(Biallelic
mutations in Alveolar GM-CSF signaling
CSF2RA 300770
Pulmonary alveolar proteinosis pseudo- macrophages
autosomal
gene)
CSFR2B AR 614370

Page 46 of 79
MDS, myelodysplastic syndrome, IUGR, intrauterine growth retardation, LAD, leukocyte adhesion deficiency, AML, acute myelogenous leukemia, CMML, chronic myelomonocytic leukemia, N= neutrophil, M=
monocyte, MEL= melanocyte, L= lymphocyte, NK= natural killer

Total number of defects in Table V: 45

New inborn errors of immunity: 4, DBF4, SRP19, SRPRA, CCR267-69

Page 47 of 79
Table VI: Defects in Intrinsic and Immunity

1. Mendelian Susceptibility to mycobacterial disease (MSMD)

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
IL-12 and IL-23 receptor 1 chain L + NK+MAIT
IL12RB1 AR 601604
deficiency
IL-12p40 (IL-12 and IL-23) deficiency IL12B AR 161561 M
L + NK+MAIT IFN- secretion
IL-12R2 deficiency IL12RB2 AR 601642 Susceptibility to mycobacteria and Salmonella and
IL-23R deficiency IL23R AR 607562 L +NK+MAIT CMC
AR 209950 M+L
IFNGR1 IFN- binding and signaling
IFN- receptor deficiency AD 615978 M+L
IFNGR2 AR 147569 M+L IFN- signaling.
STAT1 deficiency STAT1 AD LOF 614892 M+L
Macrophage gp91 phox deficiency Macrophage Respiratory burst defect in Isolated susceptibility to mycobacteria
CYBB XL 300645 only monocytes (not in neutrophils)
Q231P and T178P
M+L Impaired development of Susceptibility to mycobacteria
AD 614893
cDCs and Th1* cells
M Lack of circulating monocytes Susceptibility to mycobacteria and multiple other
IRF8 deficiency IRF8
and DCs, reduced NK cell infectious agents including EBV
AR 226990
numbers and function reported
in some patients
M+L Impaired development of Susceptibility to mycobacteria and Salmonella
SPPL2a deficiency SPPL2A AR 608238
cDCs and Th1* cells
M+L Impaired cellular responses to Susceptibility to intracellular bacteria (mycobacteria,
IL-10, IL-12, IL-23, and type I Salmonella), and viruses
TYK2 deficiency AR 611521
IFNs
TYK2
L Impaired cellular responses to MSMD or tuberculosis
P1104A TYK2 homozygosity AR 176941
IL-23
IFN production defect Susceptibility to mycobacteria (BCG), brain
ISG15 deficiency ISG15 AR 147571
calcification
L + NK Lack of functional RORT Susceptibility to mycobacteria and candida
protein, IFN production
RORt deficiency RORC AR 602943
defect, complete absence of
IL-17A/F-producing T cells
N+L Reduced JAK1 activation to Susceptibility to mycobacteria and viruses, urothelial
147795
JAK1 deficiency JAK1 AR LOF cytokines, carcinoma
Reduced IFN production

Page 48 of 79
 L IFN- and TNF-α production Susceptibility to mycobacteria
by T cells, MAIT cells, iNKT
T-bet deficiency TBX21 AR 619630
cells, NK cells, and CD4+ T
cells
L No IFN- production by patient Susceptibility to mycobacteria
IFN deficiency IFNG AR 618963
T and NK cells
Lymphocytes, IRF1-dependent responses Early onset severe forms of MSMD due to BCG,
dendritic cells, to IFN-γ are, both M. avium complex. No history of severe viral
NK, ILCP, quantitatively and illnesses. Histoplasmosis in 2 patients.
ILCP2 qualitatively, stronger than
those to IFN-α/β. IRF1-
deficient mononuclear
IRF1 deficiency IRF1 AR 620668 phagocytes do not control
mycobacteria and related
pathogens normally when
stimulated with IFN-γ while
IFN-α/β-dependent intrinsic
immunity to viruses seems
unaffected
Lymphocytes Impaired cellular responses Life-threatening early onset BCG disease.
to IIL-23 and partially IL-12, Disease was multifocal or disseminated in
MCTS1 deficiency MCTS1 XLR 301115 impaired IL-23dep IFN several cases including osteomyelitis
induction by MAIT and T
cells

2. Epidermodysplasia verruciformis (HPV)

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
EVER1 deficiency TMC6 605828 EVER1, EVER2 and CIB1
form a complex in Human papillomavirus (HPV) (group B1) infections
EVER2 deficiency TMC8 AR 605829 Keratinocytes keratinocytes and cancer of the skin (typical EV)
CIB1 deficiency CIB1 618267
WHIM (Warts, Leukocytes Increased response of the Warts (HPV) infection, neutropenia, low B cell number,
Hypogammaglobulinemia, infections, CXCR4 AD GOF 162643 CXCR4 chemokine receptor to hypogammaglobulinemia
Myelokathexis) syndrome its ligand CXCL12 (SDF-1)

3. Predisposition to Severe Viral Infection

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
Leukocytes and other cells STAT1-dependent Severe viral infections, mycobacterial infection
STAT1 deficiency STAT1 AR LOF 600555
IFN-/,  and  responses

Page 49 of 79
 Leukocytes and other cells STAT2-dependent Severe viral infections (disseminated vaccine-
STAT2 deficiency STAT2 AR 600556 IFN-/,  and  responses strain measles), influenza, HSV, enterovirus);
atypical Kawasaki Disease, HLH
147574* Leukocytes and other cells IRF9- and ISGF3-dependent
IRF9 deficiency IRF9 AR
IFN-/ and responses
Leukocytes, plasmacytoid IFN-,  and  production and Severe influenza disease
IRF7 deficiency IRF7 AR 605047 dendritic cells, non- IFN-l production
hematopoietic cells
Leukocytes and other cells IFNAR1-dependent responses to Severe viral infections (dissemination of Yellow
IFNAR1 deficiency IFNAR1 AR 107450*
IFN-/ Fever vaccine and Measles vaccine
Broadly expressed IFNAR2-dependent responses to Severe viral infections (disseminated vaccine-
IFNAR2 deficiency IFNAR2 AR 602376
IFN-/ strain measles, HHV6)
NK cells Altered NK cell function Severe herpes viral infections, particularly VZV,
CD16 deficiency FCGR3A AR 146740
Epstein Barr virus (EBV), and (HPV)
Broadly expressed Viral recognition and IFN Rhinovirus and other RNA viruses
MDA5 deficiency IFIH1 AR LOF 606951
induction
Severe (fatal) susceptibility to CMV-induced
Mutant NOS2 failed to induce disease; pneumocystis pneumonia secondary
NOS2 deficiency NOS2 AR NA
Myeloid cells nitrous oxide to CMV; intact responses to infection with other
herpes viruses (EBV, VZV, HSV)
Severe infections by RNA/DNA viruses,
mycobacteria; early-onset severe inflammation
ZNFX1 deficiency ZNFX1 AR 619644 Broadly expressed  ISG in response to poly I/C affecting liver, brain, kidneys, lungs; virally
triggered inflammatory episodes,
hepatosplenomegaly, lymphadenopathy
POLR3A AD 614258 Impaired viral recognition and
RNA polymerase III
POLR3C AD 617454 Leukocytes and other cells IFN induction in response to Severe VZV infection
deficiency
POLR3F AD 617455 VZV or poly I:C
Excessive inflammatory Multisystemic inflammatory syndrome in
Monocytic phagocytes cytokine production by children (MIS-C) after SARS-CoV2
OAS1 AR
monocytes

Monocytic phagocytes Excessive inflammatory MIS-C

cytokine production by
MIS-C OAS2 AR
monocytes

Monocytic phagocytes Excessive inflammatory MIS-C

cytokine production by
RNASEL AR
monocytes

4. Herpes Simplex Encephalitis (HSE)

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features

Page 50 of 79
 TLR3-dependent IFN-, , and  response Herpes simplex virus 1 encephalitis
AD
(incomplete clinical penetrance for all
TLR3 deficiency TLR3 613002
etiologies listed here); severe pulmonary
AR
influenza; VZV
UNC-93B-dependent IFN-, , and 
UNC93B1 deficiency UNC93B1 AR 608204
response
TRAF3 deficiency TRAF3 AD 601896 TRAF3-dependent IFN-, , and  response
AD TRIF-dependent IFN-, , and  response
TRIF deficiency TICAM1 607601 Herpes simplex virus 1 encephalitis
AR
TBK1-dependent
Central nervous system
TBK1 deficiency TBK1 AD 604834 IFN-, , and  response
(CNS) resident cells and
fibroblasts
Low IFN /, production in response to
IRF3 deficiency IRF3 AD 616532
HSV1 and decreased IRF3 phosphorylation
607024 Impaired production of anti-viral IFNs HSE of the brainstem. Other viral
DBR1 deficiency DBR1 AR
infections of the brainstem.
SNORA31 deficiency SNORA31 Impaired production of anti-viral IFNs Forebrain HSV1 encephalitis
AD 619396
ATG4A deficiency ATG4 Impaired HSV2-induced autophagy Mollaret’s meningitis (recurrent
Central nervous system →increased viral replication and apoptosis of lymphocytic meningitis) due to HSV2
MAP1LC3B2 deficiency AD NA (CNS) resident cells and patient fibroblasts
MAP1LC3B2
fibroblasts

Impaired cellular apoptosis and Herpes simplex encephalitis recurrent

necroptosis upon TLR3, TLR4, or TNFR1 in one patient. Otherwise, healthy.
RIPK3 deficiency RIPK3 AR NA Neurons stimulation and ZBP1/DAI-mediated
necroptotic cell death after HSV-1
infection
CVID phenotype, low switched memory
 RNA5SP141 expression results in B cells absent IgM. Defect in
GTF3A deficiency GTF3A AR NA Fibroblasts abrogated RIG-I activation upon HSV-1 pneumoccal antibody response. T cells
infection. mostly memory effector phenotype,
Low TFH and TH17 cells.
Impaired induction of IFN-β1 (IFNB1) Recurrent HSV-2 meningitis
upon HSV-2 infection or dsDNA
IKBKE deficiency IKBKE AD NA Microglia
stimulation. Failure to induce
phosphorylation of STING

5. Predisposition to Invasive Fungal Diseases

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
Mononuclear phagocytes CARD9 signaling pathway Invasive candidiasis infection, deep dermatophytoses, other
CARD9 deficiency CARD9 AR 607212
invasive fungal infections

Page 51 of 79
 6. Predisposition to Mucocutaneous Candidiasis
Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
Epithelial cells, fibroblasts, IL-17RA signaling pathway, and CMC, folliculitis
mononuclear phagocytes fibroblasts fail to
IL-17RA deficiency IL17RA AR 605461
respond to IL-17A and IL-17F,
and their T cells to IL-17E
IL-17RC signaling pathway, CMC
IL-17RC deficiency IL17RC AR 610925 fibroblasts fail to
respond to IL-17A and IL-17F
IL-17F deficiency IL17F AD 606496 T cells IL-17F-containing dimers CMC
T cells, B cells, NK, monocytes Increased STAT1 phophorylation CMC, various fungal, bacterial, and viral (HSV)
STAT1 GOF STAT1 AD GOF 600555 Low Th17 cells infections, auto-immunity (thyroiditis, diabetes,
cytopenias), enteropathy
T cells, fibroblasts Fibroblasts fail to CMC, blepharitis, folliculitis and macroglossia
respond to IL-17A and IL-17F,
ACT1 deficiency TRAF3IP2 AR 607043
and their T cells to IL-17E

T cells, fibroblasts  Th17 cells ex vivo, in vitro, CMC, connective tissue disorder (similar to
JNK1 haplo-  responses of fibroblasts to IL- Ehlers-Danlos syndrome)
MAPK8 AD NA
insufficiency 17A, IL-17F,  c-Jun/ATF-2-
dependant TGF β signaling

7. TLR Signaling Pathway Deficiency

Disease Genetic defect Inheritance OMIM Affected cells Affected function Associated features
Lymphocytes + TIR-IRAK4 signaling pathway
IRAK4 deficiency IRAK4 AR 606883
Granulocytes+ Monocytes
Lymphocytes + TIR-MyD88 signaling pathway Pyogenic bacterial diseases, severe viral
MyD88 deficiency MYD88 AR 602170 Granulocytes+ Monocytes diseases

Lymphocytes Loss of negative regulation recurrent episodes of fever, massive

of IRAK-4 and IRAK-1; splenomegaly, elevated inflammatory
Systemic
dysregulation of myddosome markers and severe hypochromic
autoinflammation
IRAK4 AR 607676 assembly and disassembly; or microcytic anemia
splenomegaly and
kinase active site instability may
anemia (NASA)
drive dysregulated IL-6 and TNF
production.
Lymphocytes + TLR-IRAK1 signaling pathway in Bacterial infections, X-linked MECP2
300283 Granulocytes+ Monocytes fibriblasts, TLR7- and TLR8- deficiency-related syndrome due to a large
IRAK1 deficiency IRAK1 XL
IRAK1 signaling pathway in EBV- de novo Xq28 chromosomal deletion
B cells encompassing both MECP2 and IRAK1

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 TIRAP- signaling pathway, Staphylococcal disease during childhood in
Lymphocytes + TLR1/2, TLR2/6, and TLR4 the patient lacking lipoteichoic acid (LTA)
TIRAP deficiency TIRAP AR 614382
Granulocytes+ Monocytes agonists were impaired in the Abs
fibroblasts and leukocytes
Lymphocytes, Myeloid Impaired responses to TLR7 Severe COVID19 infection
TLR7 deficiency TLR7 XL 301051 cells ligands; reduced production of
type 1 IFN
Myeloid cells Elevated proinflammatory serum Early onset, severe cytopenias,
cytokines; increased pro- hepatosplenomegaly, lymphadenopathy;
inflammatory responses of progressive autoinflammatory disease
XL / somatic
TLR8 GOF TLR8 NA patient myeloid cells to TLR8
mutations
agonists; reduced ability of
mutant TLR8 to attenuate TLR7
signaling
Myeloid cells Decreased endocytosis of very early onset inflammatory bowel
TLR4 leads to impaired NF-kB disease and recurrent infections,
MD2 deficiency LY96 AR NA
signaling and decreased pneumonia, and otitis media
cytokine production.
TLR4 deficiency TLR4 AR NA Impaired TLR4 signaling Inflammatory bowel disease

8. Other Inborn Errors of Immunity Related to Non-Hematopoietic Tissues

Disease Genetic defect Inheritance Gene OMIM Affected cells Affected function Associated features
No spleen RPSA encodes ribosomal Bacteremia (encapsulated bacteria)
RPSA AD 271400 protein SA, a component of the
small subunit of the ribosome
Isolated congenital asplenia (ICA)
Macrophages HO-1 regulates iron recycling Hemolysis, nephritis, inflammation
HMOX AR 141250 and heme-dependent damage
occurs
Trypanosomiasis APOL1 AD 603743 Somatic Pore forming serum protein Trypanosomiasis
Acute liver failure due to NBAS Somatic and ER stress Fever induces liver failure
NBAS AR 608025
deficiency hematopoietic
Ubiquitous Nuclear pore Fever induces acute encephalopathy
Acute necrotizing encephalopathy RANBP2 AD 601181
expression
Secretory lysosomes Osteopetrosis with hypocalcemia,
CLCN7 AR/AD 602727
neurologic features
SNX10 AR 614780 Osteopetrosis with visual impairment
Osteopetrosis with hypocalcemia,
Osteopetrosis OSTM1 AR 607649 Osteoclasts neurologic features
PLEKHM1 AR 611466 Osteopetrosis
TCIRG1 AR 604592 Osteopetrosis with hypocalcemia
TNFRSF11A AR 603499 Osteoclastogenesis Osteopetrosis

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 Stromal Osteoclastogenesis Osteopetrosis with severe growth
TNFSF11 AR 602642
retardation
605254 Notch signaling/ Gamma- Verneuil’s disease/ Hidradenitis suppurativa
NCSTN AD
secretase in hair follicle with acne
Hidradenitis suppurativa regulates keratinization Verneuil’s disease/ Hidradenitis suppurative
PSEN AD 613737
Epidermis with cutaneous hyperpigmentation
PSENEN AD 613736 Verneuil’s disease/ Hidradenitis suppurativa

9. Other Inborn Errors of Immunity Related to Leukocytes

Disease Genetic defect Inheritance Gene OMIM Affected cells Affected function Associated features
601900 Lymphocytes IRF4 is a pleiotropic transcription Whipple’s disease
IRF4 haploinsufficiency IRF4 AD
and Monocytes factor
Leukocytes and IL-18BP neutralizes secreted IL- Fulminant viral hepatitis
IL-18BP deficiency IL18BP AR 604113
other cells 18
Monocytes + Multi lineage cytopenia Susceptibility to mycobacteria, HPV,
GATA2 deficiency GATA2 AD 137295 peripheral DC, histoplasmosis, alveolar proteinosis,
NK cells MDS/AML/CMML, lymphedema
NF-B, nuclear factor kappa B, TIR, Toll and Interleukin 1 Receptor, IFN, interferon, TLR, Toll-like receptor, MDC, myeloid dendritic cell, CNS, central nervous system, CMC, chronic mucocutaneous candidiasis,
HPV, human papilloma virus, VZV, varicella zoster virus, EBV, Epstein Barr virus

Total number of mutant genes in Table VI: 86 diseases with 2 entries for IRAK4 counted separately as they constitute different genetic mechanisms and associated phenotypes. GATA2 was moved from
non-lymphoid disease table to table VI.9.

New inborn errors of immunity: 10 (IRF1, MCTS1, OAS1, OAS2, RNASEL, RIPK3, MD2, TLR4, GTF3A, IKBKE) 70-77

Page 54 of 79
Table VII: Autoinflammatory Disorders

1. Type 1 Interferonopathies

Disease Genetic defect Inheritance OMIM T Cells B cells Functional defect Associated Features

STING activates both the NF-

AD STING-associated
kappa-B and IRF3 transcription Skin vasculopathy, inflammatory lung disease,
vasculopathy, infantile- AD 612374 Not assessed Not assessed
pathways to induce expression of systemic autoinflammation and ICC, FCL
onset (SAVI)
TMEM173** IFN
(STING)
STING activates both the NF- FTT, early onset rash, fever, dyspnea, interstitial lung
AR STING-associated
kappa-B and IRF3 transcription disease/pneumonitis, polyarthritis, autoAbs,
vasculopathy, infantile- AR GOF 615934 Not assessed Not assessed
pathways to induce expression of increased inflammatory markers, IFN gene signature.
onset (SAVI)
IFN Phenocopy of SAVI due to AD GOF TMEM173

ADAs deactivate extracellular

Polyarteritis nodosa, childhood-onset, early-onset
adenosine and terminate
ADA2 deficiency ADA2 AR 607575 Not assessed Not assessed recurrent ischemic stroke and fever; some patients
signaling through adenosine
develop hypogammaglobulinemia
receptors
Intracellular accumulation of
TREX1 deficiency,
AR abnormal ss DNA species
Aicardi-Goutieres TREX1 606609 Not assessed Not assessed Classical AGS, SLE, FCL
leading to increased type I IFN
syndrome 1 (AGS1) AD
production
RNASEH2B deficiency,
RNASEH2B AR 610326 Not assessed Not assessed Classical AGS, SP
AGS2
Intracellular accumulation of
RNASEH2C deficiency, abnormal RNA-DNA hybrid
RNASEH2C AR 610330 Not assessed Not assessed Classical AGS
AGS3 species leading to increased type
I IFN production
RNASEH2A deficiency,
RNASEH2A AR 606034 Not assessed Not assessed Classical AGS
AGS4
Controls dNTPs in the cytosol,
SAMHD1 deficiency,
SAMHD1 AR 606754 Not assessed Not assessed failure of which leads to Classical AGS, FCL
AGS5
increased type I IFN production
Catalyzes the deamination of
adenosine to inosine in dsRNA
ADAR1 deficiency,
ADAR1 AR 146920 Not assessed Not assessed substrates, failure of which leads Classical AGS, BSN, SP
AGS6
to increased type I IFN
production
IFIH1 gene encodes a
Aicardi-Goutières
IFIH1 AD GOF 615846 Not assessed Not assessed cytoplasmic viral RNA receptor Classical AGS, SLE, SP, SMS
syndrome 7 (AGS7)
that activates type I interferon

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 signaling through the MAVS
adaptor molecule
DNAse II degrades and
eliminates DNA. Loss of DNase II
DNAse II deficiency DNASE2 AR 126350 Not assessed Not assessed AGS
activity induces type I interferon
signaling
LSM11 deficiency Not Increased IFN signaling in
LSM11 AR 619486 Not assessed AGS, type 1 IFN-opathy
(2 patients) assessed fibroblasts
RNU7-1 deficiency Not Increased IFN signaling in
RNU7-1 AR 619487 Not assessed AGS, type 1 IFN-opathy
(16 patients) assessed fibroblasts
Pediatric systemic DNASE1L3 is an endonuclease Very early onset SLE, reduced complement levels,
lupus erythematosus that degrades extracellular DNA. autoantibodies (dsDNA, ANCA), lupus nephritis,
DNASE1L3 AR 614420
due to DNASE1L3 DNASE1L3 deficiency decreases hypocomplementemic urticarial vasculitis syndrome
deficiency clearance of apoptotic cells
Spondyloenchondro-
Upregulation of IFN through Short stature, SP, ICC, SLE, thrombocytopenia and
dysplasia with immune
ACP5 AR 171640 Not assessed Not assessed mechanism possibly relating to autoimmune hemolytic anaemia, possibly recurrent
dysregulation
pDCS bacterial and viral infections
(SPENCD)
Defective negative regulation of TORCH like syndrome, autoinflammation and
USP18 deficiency USP18 AR 607057 Not assessed Not assessed
ISG15 leading to increased IFN mycobacterial disease
164350 Increased interferon from
OAS1 GOF OAS1 AD GOF Low Pulmonary alveolar proteinosis, skin rash
recognition of RNA
Neonatal onset: pancytopenia, fever, rash,
serum levels of IL1, IL18, IFN-,
hepatosplenomegaly, multisystemic inflammation,
CDC42 deficiency Normal/ Normal/ ferritin, sCD25, CRP etc.
CDC42 AD 616737 myelofibrosis/proliferation, HLH, enterocolitis;
decreased decreased Mutation affects actin function, 
Recurrent GIT/URT infections; neurodevelopmental
NK cell cytotoxicity
delay, FTT
Patient cells hyper-sensitive to
IFN-α, GOF for induction of the
late (not early) response to type 1 Severe fatal early onset autoinflammation, serum
STAT2 R148
STAT2 AR 616636 Increased Normal IFNs due to impaired interaction IFN-α, IL6, TNF, phenocopy of USP18 deficiency
LOF/regulation
of mutant STAT2 with USP18, a
negative regulator of type 1 IFN
responses
ATAD3A deficiency Elevated ISG expression, Predominantly neurological defects (development
ATAD3A AD/AR 617183 Not assessed Not assessed
increased serum type 1 IFNs delay, spasticity)
Disabling pansclerotic
Low CD4 T Not Unstimulated fibroblasts Skin sclerosis, poor wound healing, joint
morphea of childhood STAT4 AD GOF 620443
cells assessed produce high levels of IL-6. contractures, mucosal ulcerations
(DPMC)
Chronic mucocutaneous ulceration,
RELA Normal/
RELA AD 618287 Normal Impaired NF-B activation; reduced production of
Haploinsufficiency increased
inflammatory cytokines
The patients with RELA DN mutations shared
Leukocytes TLR7-dependent
RELA interferonopathy* RELA AD DN 618287 clinical phenotypes with RELA
typeI/III IFN production.
haploinsufficiency, presenting chronic

Page 56 of 79
 mucocutaneous ulcerations and autoimmune
hematological disorders such as immune
thrombocytopenia (ITP) and neutropenia.
However, patients with RELA DN mutations
additionally presented periodic fever,
inflammatory bowel disease (IBD) juvenile
idiopathic arthritis (JIA), and skin involvement.

2. Defects Affecting the Inflammasome

Affected
Disease Genetic defect Inheritance OMIM Functional defects Associated Features
cells
Mature
granulocytes,
Increased pyrin inflammasome-mediated Recurrent fever, serositis
AR LOF 249100 cytokine-
induction of IL1. and inflammation
activated
monocytes. responsive to colchicine.
Familial Mediterranean fever (FMF) MEFV** Predisposes to vasculitis
Mature and inflammatory bowel
granulocytes, Usually, M694del variant. Other missense disease, SAA
AD 134610 cytokine- variants in the B-Box and CC domains cause amyloidosis.
activated constitutive pyrin activation
monocytes.

Pyogenic sterile arthritis, pyoderma gangrenosum, acne Activation of the pyrin inflammasome; high Destructive arthritis,
PMNs,
(PAPA) syndrome, hyperzincemia and PSTPIP1 AD 604416 production of IL-1 and IL-18 cytokines; inflammatory skin rash,
monocytes
hypercalprotectinemia interferon signature myositis

Defect in production of isoprenoids, which are

Periodic fever and
Mevalonate kinase deficiency (Hyper IgD syndrome/ Somatic and synthesized via mevalonate pathway and
MVK AR 260920 leukocytosis with usually
HIDS) hematopoietic play a role in regulation of many signaling
high IgD levels
pathways.
Recurrent fever
episodes, arthritis, and
PMVK deficiency PMVK AR NA Leukocytes Similar to MVK deficiency, increased IL1-
cytopenia

PMNs Urticaria, SNHL, SAA

Muckle-Wells syndrome NLRP3** AD GOF 191900
Monocytes amyloidosis.

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 Activation of cryopyrin inflammasome results Non-pruritic urticaria,
Familial cold in increased production of IL-1/IL-18
PMNs, arthritis, chills, fever, and
autoinflammatory syndrome 1 AD GOF 120100 cytokines and cell death via pyroptosis.
monocytes leukocytosis after cold
exposure.

Neonatal onset rash,

Neonatal onset multisystem inflammatory disease
PMNs, chronic meningitis, and
(NOMID) / chronic infantile neurologic cutaneous and AD GOF 607115
chondrocytes arthropathy with fever
articular syndrome (CINCA)
and inflammation.

Episodic conjunctival
injection, ocular pain,
Keratitis fugax hereditaria photophobia, foreign
associated to c.61G>C AD GOF 606416 body sensation, and
NLRP3 excessive tearing during
acute attacks. Corneal
opacities during attacks.
Non-pruritic urticaria,
Familial cold PMNs, arthritis, chills, fever, and
NLRP12 AD GOF 611762
autoinflammatory syndrome 2 monocytes leukocytosis after cold
exposure.
PMNs
NLRC4-MAS (macrophage activating syndrome) 616050 monocytes Gain of function mutation in NLRC4 results in Severe enterocolitis and
NLRC4 AD GOF macrophages, elevated secretion of IL-1β and IL-18 as well macrophage activation
intestinal as macrophage activation syndrome
Familial cold autoinflammatory syndrome 4 616115 epithelial cells

APLAID or autoinflammation, antibody deficiency and Missense 614878

immune dysregulation variants Cold urticaria
hypogammaglobulinemia,
Mutations affect the autoinhibitory domains
AD GOF/ B cells, NK, impaired humoral
and activate NF-kB and MAPK
PLCG2 LOF Mast cells immunity, autoantibodies,
pathways
autoinflammation,
PLAID or Familial cold autoinflammatory syndrome 3 small intragenic 614468 granulomas
deletions

Keratinocytes Systemic elevation of IL-18, IL1β, caspase 1, Dyskeratosis,

Autoinflammation with arthritis and dyskeratosis
NLRP1 AR 617388 and suggesting activation of NLRP1 autoimmunity and
(AIADK; NLRP1 deficiency)
leukocytes inflammasome arthritis
Spontaneous production of IL1β and IL-18 Palmoplantar carcinoma,
NLRP1 GOF NLRP1 AD GOF 615225 Keratinocytes
cytokines in keratinocytes corneal scarring;

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 recurrent respiratory
papillomatosis
Long-lasting fever
episodes
Autoinflammation with episodic fever and Leukocytes
TNF-induced cell death via apoptosis and lymphadenopathy,
lymphadenopathy / Cleavage resistant RIPK1-induced RIPK1 AD 618852 and
necroptosis spleno/hepatomegaly,
Autoinflammatory syndrome/ CRIA fibroblasts
ulcers, arthralgia, GI
features
Chronic recurrent
Dysregulation in cholesterol synthesis impairs
Neutrophils, multifocal osteomyelitis,
Chronic recurrent multifocal osteomyelitis and the negative regulation of NLRP3 in
LPIN2 AR 609628 bone marrow transfusion-dependent
congenital dyserythropoietic anemia (Majeed syndrome) macrophages resulting in high production of
cells anemia, cutaneous
IL-1
inflammatory disorders

Page 59 of 79
 3. Non-Inflammasome Related Conditions
Genetic
Disease Inheritance OMIM Affected cells Functional defects Associated Features
defect
Mutations in the extracellular domain of
55-kD TNF receptor cause protein
TNF receptor-associated Recurrent fever, serositis, rash, and ocular or
TNFRSF1A** AD 142680 PMNs, monocytes misfolding and intracellular receptor
periodic syndrome (TRAPS) joint inflammation
retention resulting in upregulation of ER
stress

Mutations in nucleotide binding site of

Uveitis, granulomatous synovitis,
Monocytes, intestinal CARD15 result in constitutive activation
Blau syndrome NOD2** AD 186580 camptodactyly, rash, and cranial neuropathies,
epithelial cells of NOD2 nodosome and upregulation of
30% develop Crohn colitis
NF-kB signaling

Leukocytes and
ADAM17 deficiency ADAM17 AR 614328 Defective TNFα production Early onset diarrhea and skin lesions
epithelial cells

DIRA (Deficiency of the Mutations in the IL1 receptor antagonist

Neonatal onset of sterile multifocal
Interleukin 1 Receptor IL1RN AR 612852 PMNs, Monocytes allow unopposed action of IL-1α and IL-
osteomyelitis, periostitis and pustulosis
Antagonist) 1β

Loss of IL-1R1 sensitivity to

Activated myeloid cells. Loss of IL-1R1 Arthritis, osteolytic/sclerotic bone lesions, poor
IL-Ra (LIRSA/CRMO3) (1 IL-1R1 AD 259680 T cells and B cells
biding to endogenous IL-Ra growth, no rash, no fever
patient)
Mutations in the IL36 receptor antagonist
DITRA (Deficiency of IL-36 Keratinocytes,
IL36RN AR 614204 allow unopposed action of IL-1α and IL- Pustular psoriasis
receptor antagonist) leukocytes
1β
Histiocytosis- Hyperpigmentation hypertrichosis,
Defect in nucleoside transport functions
lymphadenopathy plus Leukocytes, hepatosplenomegaly, heart anomalies, hearing
SLC29A3 AR 602782 of hENT3 leads to histiocytic infiltration of
syndrome /H syndrome histiocytes loss, hypogonadism, low height, and
numerous organs
(ENT3) occasionally hyperglycemia/diabetes mellitus
CAMPS (CARD14 mediated Mainly in Mutations in CARD14 activate the NF-kB
CARD14 AD 602723 Psoriasis
psoriasis) keratinocytes pathway and production of IL-8
Stroma cells, bone Hyperactived macrophages and
Cherubism SH3BP2 AD 118400 Bone degeneration in jaws
cells osteoclasts, increased NF-kB signaling
PRAAS-CANDLE (chronic Keratinocytes, B cell Proteasome dysfunction with
PSMB8* AR and AD 256040 Contractures, panniculitis, ICC, fevers
atypical neutrophilic adipose cells accumulation of ubiquitinated proteins

Page 60 of 79
dermatitis with 609702 and ER stress. Increased interferon Panniculitis, lipodystrophy, autoimmune
lipodystrophy) PSMG2 AR Lymphocytes signature hemolytic anemia
Proteasome dysfunction with periorbital and hands feet annular rash
accumulation of ubiquitinated proteins (neutrophilic dermatosis), microcytic anemia,
PSMB10 AR 619175 Lymphocytes
and ER stress. Increased interferon long slender fingers, hepatomegally and
signature splenomegaly
Proteasome dysfunction with
AR or
accumulation of ubiquitinated proteins
PSMB9 Digenic or 617591 Lymphocytes
and ER stress. Increased interferon
DN
signature
Proteasome dysfunction with
AR or accumulation of ubiquitinated proteins Panniculitis, lipodystrophy, autoimmune
PSMB4 617591 Lymphocytes
Digenic and ER stress. Increased interferon hemolytic anemia
signature
CANDLE (chronic atypical neutrophilic
Increased accumulation of ubiquitinated dermatitis with lipodystrophy)/, Interstitial lung
proteins and ER stress with increased disease in one patient, liver disease in one
PRAID POMP AD 618048 Lymphocytes
IFN signaling mediated by increased patient. Recurrent and opportunistic infections.
PKR signaling Low CD8 T cells, skewing towards naive T
cells. Low B cells and positive autoantibodies.
Decreased protein expression and Severe autoinflammatory phenotype (neonatal-
reduced proteasome activities. Elevated onset fever, skin rash, myositis, severe
AD (DN Leukocytes (Mild levels of inflammatory cytokines (IL-6, IL- pulmonary hypertension, basal ganglia
PSMB9 deficiency (G156D) PSMB9 617591 calcification), periodic inflammatory
LOF) pancytopenia) 18, IP-10, IFN), liver enzymes in blood
and CSF (IFN), hyperactivation of IFN- exacerbation; immunodeficiency. Partial
, pSTAT1, phenocopy of PRAAS
Autoinflammation with ↑ peripheral blood type I IFN gene
Intellectual disability, developmental delay,
neurodevelopmental PSMD12 AR 617516 CNS, lymphocytes signature has been reported for some
urticarial skin rash, elevated interferon signature
disease patients
Autoimmune inflammatory arthritis and
PMN and tissue Defective intracellular transport via the
COPA Syndrome COPA AD 6011924 interstitial lung disease with Th17 dysregulation
specific cells coat protein complex I (COPI)
and autoantibody production
Increase LUBAC induction of NF-KB and
Leukocytes, interferon activation leading to high
Otulipenia/ORAS OTULIN AR/AD 615712 Fever, diarrhea, skin abscesses, panniculitis
fibroblasts proinflammatory cytokines levels.
Increase in TNF-induced cell death
Decreased catalytic activity,
Dominant negative OTULIN
Lymphocytes and accumulation of linear ubiquitin
related autoinflammatory OTULIN AD 615712 Spontaneous systemic inflammation
fibroblasts chains, increased TNF induced cell
syndrome (3 patients)
death,
Increased activity of caveolin-1
Susceptibility to Staphyloccus aureus
OTULIN haploinsufficiency OTULIN AD 615712 Epithelial cells stabilizes ADAM10 receptor for S.
infections in epithelial cells
Aureus toxin

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Haploinsufficiency of A20/ Defective inhibition of NF-KB signaling
TNFAIP3 AD 616744 Lymphocytes Arthralgia, mucosal ulcers, ocular inflammation
HA20 pathway
AP1S3 deficiency AP1S3 AR 615781 Keratinocytes Disrupted TLR3 translocation Pustular psoriasis
171740 Intestinal epithelial
ALPI deficiency ALPI AR Deficient inhibition of LPS in intestine Inflammatory bowel disease
cells
Macrophages,
606559
TRIM22 TRIM22 AR intestinal epithelial Granulomatous colitis Inflammatory bowel disease
cells
T-cell lymphoma
618398 Increased inflammasome activity due to Panniculitis, HLH, polyclonal cutaneous T cell
subcutaneous panniculitis- HAVCR2 AR Leukocytes
defective checkpoint signaling infiltrates or T-cell lymphoma
like (TIM3 deficiency)
Early onset severe autoinflammation disorder,
C2orf69 regulates mitochondrial function;
C2orf69 deficiency Outer mitochondrial often fatal. Global developmental delay, with
C2orf69 AR 619423 protein deficiency causes respiratory
(28 patients) membrane of all cells recurrent seizures, Muscle weakness due to
chain defects
glycogen deposits
Increased SYK phosphorylation,
enhanced NF-kB, JNK, and ERK
Recurrent infections, multi-organ
signaling. Mutated T cells are hyper-
Lymphocytes, inflammation/inflammatory disease (gut, skin,
SYK GOF SYK AD GOF 619381 sensitive to stimulation and produce
osteoclasts CNS, lung, liver), B cell lymphoma reported in 2
various proinflammatory chemokines and
pts
cytokines (IL-17, IL-22, TNF, IFNg)

Increased kinase activity of HCK mutant Cutaneous vasculitis, inflammatory leukocyte

HCK GOF HCK AD GOF 620296 Lymphocytes in vitro;  production of inflammatory infiltration of the lungs (pulmonary fibrosis) and
cytokines (IL-1, IL-6, IL-8, TNF-), ROS skin, anemia, hepatosplenomegaly
Mutant NEMO lacks exon 5 (NEMO- Fever, skin rash, systemic autoinflammation,
Dex5), fails to bind TBK1; NEMO-Dex5 infections, CNS involvement, panniculitis,
NEMO exon 5 deletion IKBKG XL 301081 Leukocytes
stabilized IKKi, strong NF-kB and uveitis, hepatosplenomegaly, ectodermal
interferon gene expression signatures dysplasia
Chronic systemic autoinflammation
Autoinflammation driven by TNF-induced
TBK1 deficiency TBK1 AR NA Leukocytes (polyarthritis, vasculitis, rash); delayed
RIPK1-dependent cell death
neurocognitive development
Retinal dystrophy, optic Immune activation with increased NF- Retinal dystrophy, optic nerve edema,
nerve oedema, 614979 κB signaling, STAT1 phosphorylation splenomegaly, anhidrosis, and migraine
ALPK1 AD Lymphocytes
splenomegaly, anhidrosis, and interferon gene expression headache, fever, arthritis, colitis, dental
and headache (ROSAH) signature abnormalities
Diffuse purpuric rash/atopic dermatitis,
LYN GOF
620376 fever, hepatosplenomegaly, liver fibrosis/
Systemic autoinflammatory Endothelial cells Activated endothelial cells,
LYN AD GOF calcifications, arthritis, periorbital oedema,
disease with vasculitis, and neutrophils constitutively active neutrophils
respiratory insufficiency, colitis, poor
SAIDV
growth.
Impaired
Defect in LUBAC function, attenuated
development of
SHARPIN deficiency SHARPIN AR NA canonical NF-κB responses, Arthritis, fever, colitis, amylopectinosis
germinal centers in
increased TNF-induced cell death
secondary lymphoid

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 organs, low CD20+
cells, increased
memory B cells

IFN, interferon, HSM, hepatosplenomegaly, CSF, cerebrospinal fluid, SLE, systemic lupus erythematosus, TORCH, toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections, SNHL, sensorineural hearing
loss, AGS, Aicardi-Goutières syndrome, BSN, Bilateral striatal necrosis, FCL, familial chilblain lupus, ICC, intracranial calcification, IFN, interferon type I, pDCs, Plasmacytoid dendritic cells, SP, Spastic paraparesis,
SMS, Singleton-Merten syndrome, ss, Single-stranded DNA

*Variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8, PSMB9/PSMB4,
PSMB4/PSMB8) and AD monogenic (POMP) models 112.Only G156D mutation in PSMB9 has been shown to cause an autoinflammatory phenotype with immunodeficiency in patients and mouse model. 113

Total number of disorders in Table VII: 68

New inborn errors of immunity: 10: STAT4 GOF, PMVK, ALPK1, LYN GOF, SHARPIN, LSM11, RNU71, OTULIN (two new entries), RELA78-87
*RELA previously described causing combined immunodeficiency a second entry included here as DN mutations are associated to an inflammatory phenotype with different mechanism of disease. Otulin is repeated 3
times as different mechanisms of disease give rise to different phenotypes. NLRP1 is also repeated twice as AR and AD forms result in different phenotypes.

Page 63 of 79
Table VIII: Complement Deficiencies

Complement Deficiencies
Disease Genetic defect Inheritance Gene OMIM Laboratory features Associated features

C1QA AR 120550 Absent CH50 hemolytic activity, defective SLE, infections with encapsulated organisms
C1q deficiency due to defects C1QB AR 120570 activation of the classical pathway, diminished
C1QC AR 120575 clearance of apoptotic cells
Absent CH50 hemolytic activity, defective SLE, infections with encapsulated organisms,
C1r deficiency C1R AR 613785
activation of the classical pathway Ehlers Danlos phenotype
C1r Periodontal Ehlers Danlos C1R AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility
Absent CH50 hemolytic activity, defective SLE, infections with encapsulated organisms,
C1s deficiency C1S AR 613785
activation of the classical pathway Ehlers Danlos phenotype
C1s Periodontal Ehlers Danlos C1S AD GOF 613785 Normal CH50 Hyperpigmentation, skin fragility
Absent CH50 hemolytic activity, defective SLE, infections with encapsulated organisms,
activation of the classical pathway, complete partial deficiency is common (either C4A or C4B)
Complete C4 deficiency C4A+C4B AR 120810 deficiency requires biallelic and appears to have a modest effect on host
mutations/deletions/conversions of both C4A defense
and C4B
Absent CH50 hemolytic activity, defective SLE, infections with encapsulated organisms,
C2 deficiency C2 AR 217000
activation of the classical pathway atherosclerosis
Absent CH50 and AH50 hemolytic activity, Infections, glomerulonephritis, atypical
C3 deficiency (LOF) C3 AR 120700 defective opsonization, defective humoral hemolytic-uremic syndrome with GOF mutations
immune response
C3 GOF C3 AD GOF 120700 Increased activation of complement Atypical hemolytic-uremic syndrome
Absent CH50 and AH50 hemolytic activity
C5 deficiency C5 AR 120900
Defective bactericidal activity
C6 deficiency C6 AR 217050
C7 deficiency C7 AR 217070
Absent CH50 and AH50 hemolytic activity,
C8 deficiency C8A AR 120950 defective bactericidal activity Disseminated neisserial infections.
C8 deficiency C8G AR 120930
C8 deficiency C8B AR 120960
Reduced CH50 and AP50 hemolytic activity, Mild susceptibility to disseminated neisserial
C9 deficiency C9 AR 120940 deficient bactericidal activity infections

Deficient activation of the lectin activation Pyogenic infections, inflammatory lung disease,
MASP2 deficiency MASP2 AR 605102
pathway autoimmunity
Absence of complement activation by the Respiratory infections, abscesses
Ficolin 3 deficiency FCN3 AR 604973
Ficolin 3 pathway.
Spontaneous activation of the complement Hereditary angioedema
C1 inhibitor deficiency SERPING1 AD/AR 606860 pathway with consumption of C4/C2,
spontaneous activation of the contact system

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 with generation of bradykinin from high
molecular weight kininogen
Gain-of-function mutation with increased Atypical haemolytic-uremic syndrome
Factor B GOF CFB AD GOF 612924
spontaneous AH50
Factor B deficiency CFB AR 615561 Deficient activation of the alternative pathway Infections with encapsulated organisms
Factor D deficiency CFD AR 134350 Absent AH50 haemolytic activity Neisserial infections
Properdin deficiency CFP XL 300383 Absent AH50 haemolytic activity Neisserial infections
Spontaneous activation of the alternative
Factor I deficiency CFI AR 217030
complement pathway with consumption of C3
Spontaneous activation of the alternative Infections, disseminated Neisseria infections,
Factor H deficiency CFH AR or AD 134370 complement pathway with consumption of C3 atypical Haemolytic-uremic syndrome,
preeclampsia
CFHR1 134371, Normal CH50, AH50, autoantibodies to Factor
CFHR2 600889, H., linked deletions of one or more CFHR Older onset atypical haemolytic-uremic
Factor H –related protein deficiencies CFHR3 AR or AD 605336, genes leads to susceptibility autoantibody- syndrome, disseminated Neisseria infections
CFHR4 605337, mediated aHUS
CFHR5 608593
Thrombomodulin deficiency THBD AD 188040 Normal CH50, AH50 Atypical haemolytic-uremic syndrome
Membrane Cofactor Protein (CD46) Inhibitor of complement alternate pathway, Atypical haemolytic-uremic syndrome, infections,
CD46 AD/AR 120920
deficiency decreased C3b binding preeclampsia
Membrane Attack Complex Inhibitor (CD59) Erythrocytes highly susceptible to complement- Haemolytic anaemia, polyneuropathy
CD59 AR 107271
deficiency mediated lysis
125240 Hyperactivation of complement on endothelium Protein losing enteropathy, thrombosis
CD55 deficiency (CHAPEL disease) CD55 AR
MAC, Membrane attack complex, SLE, systemic lupus erythematosus

Total number of mutant genes in Table VIII: 36

New disorders: None

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Table IX: Bone Marrow Failure

1. Bone Marrow Failure

Other
Disease Genetic defect Inheritance Gene OMIM T cells B cells affected Associated features Major Category Subcategory
cells
Fanconi Anemia FANCA AR 227650
Type A

Fanconi Anemia FANCB XLR 300514

Type B
Fanconi Anemia FANCC AR 227645
Type C

Fanconi Anemia BRCA2 AR 605724

Type D1

Fanconi Anemia FANCD2 AR 227646

Type D2

Fanconi Anemia FANCE AR 600901

Type E

Fanconi Anemia FANCF AR 603467

Type F

Fanconi Anemia FANCG/XRCC9 AR 614082

Type G
normal to low NK, CNS, Bone marrow
Fanconi Anemia FANCI AR 609053 skeletal, skin, cardiac, GI, failure with
Type I normal to low normal to low HSC urogenital anomalies, immune Fanconi Anemia
increased chromosomal deficiency
Fanconi Anemia BRIP1 AR 609054 breakage
Type J
Fanconi Anemia FANCL AR 614083
Type L
Fanconi Anemia FANCM AR 618096
Type M
Fanconi Anemia PALB2 AR 610832
Type N

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Fanconi Anemia RAD51C AR 613390
Type O
Fanconi Anemia SLX4 AR 613951
Type P
Fanconi Anemia ERCC4 AR 615272
Type Q
Fanconi Anemia RAD51 AR 617244
Type R

Fanconi Anemia BRCA1 AR 617883

Type S
Fanconi Anemia UBE2T AR 616435
Type T
Fanconi Anemia XRCC2 AR 617247
Type U
Fanconi Anemia MAD2L2 AR 617243
Type V

Fanconi Anemia RFWD3 AR 617784

Type W

MIRAGE SAMD9 AD GOF 617053 Not reported Not reported HSC, Intrauterine growth retardation,
(myelodysplasia, myeloid gonadal abnormalities, adrenal
infection, cells failure, MDS with chromosome
restriction of 7 aberrations, predisposition to
growth, adrenal infections, enteropathy, absent
hypoplasia, spleen
genital
phenotypes,
enteropathy)
Ataxia SAMD9L AD GOF 611170 Normal low HSC, MDS, neurological features
Pancytopenia myeloid
Syndrome cells
DKCX1 DKC1 XL 305000 Bone marrow failure,
pulmonary and hepatic fibrosis,
DKCA1 TERC AD 127550 nail dystrophy, leukoplakia,
reticulate skin pigmentation;
DKCA2 TERT AD/AR 187270 microcephaly,
neurodevelopmental delay
DKCA3 TINF2 AD 604319

DKCA4 RTEL1 AD 616373

DKCA5 TINF2 AD 268130

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 DKCA6 ACD AD 616553

Normal to low Normal to low HSC Dyskeratosis

DKCB1 NOP10/NOLA3 AR 224230 Congenita

DKCB2 NHP2/NOLA2 AR 613987

DKCB3 WRAP53 AR 613988

DKCB4 TERT AR 613989

DKCB5 RTEL1 AR 615190 low Nail dystrophy, leukoplakia,

bone marrow failure, severe B-
cell immunodeficiency,
intrauterine growth retardation,
growth retardation,
microcephaly, cerebellar
hypoplasia, and esophageal
dysfunction
DKCB6 PARN AR 616353 Normal to low Developmental delay,
microcephaly, and cerebellar
hypoplasia
DKCB7 ACD AR 616553 Normal to low Bone marrow failure,
pulmonary and hepatic fibrosis,
nail dystrophy, leukoplakia,
reticulate skin pigmentation;
microcephaly,
neurodevelopmental delay
BMFS1 (SRP72- SRP72 AD 602122 NA NA Bone marrow failure and
deficiency) congenital nerve deafness
BMFS2 ERCC6L2 AR 615667 NA NA Bone marrow failure, learning
difficulties, microcephaly
BMFS5 TP53 AD 618165 NA low B Erythroid hypoplasia, B-cell
deficiency
STN1 AR 613129 Normal Normal Intrauterine growth retardation,
Coats plus premature aging,
syndrome pancytopenia, hypocellular
CTC1 AR 617053 Not reported Not reported bone marrow, gastrointestinal
hemorrhage due to vascular
ectasia, intracranial
calcification, abnormal
telomeres
MECOM MECOM AD 616738 Not reported B cell Bone marrow failure,
deficiency deficiency thrombocytopenia/pancytopeni

Page 68 of 79
 a, radioulnar synostosis,
clinodactyly, cardiac, and renal
malformations
Dyskeratosis DCLRE1B AR NA Normal to low, B cell Low Early-onset hypocellular
Congenita, Reduced deficiency neutrophils bone marrow failure, B and
Høyeraal- CD45RA in n:1 NK lymphopenia,
Hreidarsson developmental anomalies,
Syndrome microcephaly, and/or
intrauterine growth
retardation

BMF, DUT AR NA NA NA HSC, Diabetes

macrocytosis, stromal
leukemia cells
Nijmegen RAD50 AR 613078 Low T cell counts B cell Microcephaly, mental Progressive
breakage normal T cell deficiency retardation, bird-like face, BMF and
syndrome-like proportions short stature. immunodeficie
disorder and ncy
proliferation

HSC: hematopoietic stem cell; NK: natural killer; CNS: central nervous system; GI: gastrointestinal; MDS: myelodysplastic syndrome, DKCX: X-inked dyskeratosis congenital; DKCA: autosomal dominant dyskeratosis congenita;
DKCB: autosomal recessive dyskeratosis congenita; BMFS: bone marrow failure syndrome

Total number of mutant genes in Table IX: 47

New Inborn errors of immunity: 3 (SNM1B/DCLRE1B (Apollo), DUT, RAD50) 92,114,115

Table X: Phenocopies of Inborn Errors of Immunity associated with autoantibodies or somatic variants

1. Phenocopies of Inborn Errors of Immunity

Genetic defect/presumed Circulating B
Disease Circulating T cells Serum Ig Associated features/similar PID
pathogenesis cells

Associated with somatic mutations

Increased CD4-CD8- Splenomegaly, lymphadenopathy, autoimmune

Autoimmune lymphoproliferative syndrome Normal, but Normal or
Somatic mutation in TNFRSF6 double negative (DN) cytopenias, Defective lymphocyte apoptosis/ALPS–FAS
(ALPS–SFAS) increased increased
T cells (=ALPS)

Page 69 of 79
 number of
CD5+ B cells
RAS-associated autoimmune leukoproliferative Somatic mutation in KRAS B cell Normal or Splenomegaly, lymphadenopathy, autoimmune
Normal
disease (RALD) (GOF) lymphocytosis increased cytopenias, granulocytosis, monocytosis/ALPS-like

Increased
RAS-associated autoimmune leukoproliferative Somatic mutation in NRAS CD4−CD8−double Normal or Splenomegaly, lymphadenopathy, autoantibodies/ALPS-
Lymphocytosis
disease (RALD) (GOF) negative (DN) T increased like
alpha/beta cells

Cryopyrinopathy, (Muckle-Wells
Somatic mutation in NLRP3 Normal Normal Normal Urticaria-like rash, arthropathy, neurological signs
/CINCA/NOMID-like syndrome)
Hypereosinophilic syndrome due to somatic Somatic GOF mutation in
Normal Normal Normal Eosinophilia, atopic dermatitis, urticarial rash, diarrhea
mutations in STAT5b STAT5B
Late onset treatment-refractory inflammatory syndrome
VEXAS (vacuoles, E1 enzyme, X-linked, Somatic GOF mutation in (fevers, neutrophilic dermatosis, macrocytic anaemia,
Lymphopenia Reduced Normal
autoinflammatory, somatic) syndrome UBA1 (XL) dysplastic bone marrow, interstitial nephritis, chondritis,
vasculitis)
 (mild) CD4+, CD8+ T
Normal B Normal/lo Severe cytopenias, hepatosplenomegaly,
TLR8 GOF Somatic GOF mutation in cells, effector/memory
cells/subsets, IgG,  lymphadenopathy; recurrent infections; hypocellular
TLR8 subsets; NK cells
 pDCs IgM/IgA bone marrow, elevated proinflammatory serum cytokines
Asymmetric pustular rash (inflammatory linear
Upregulated
Upregulated STAT3 verrucous epidermal nevus) chronic GI tract
Somatic GOF mutation in STAT6
JAK1 GOF (S703I) Phosphorylation in T inflammation, eosinophilic colitis. Peripheral
JAK1 phosphorylati
cells eosinophilia. Membranous glomerulonephritis,
on
asthma.

Associated with autoantibodies

AutoAb to IL-17A and/or IL- Endocrinopathy, chronic mucocutaneous

Chronic mucocutaneous candidiasis Normal Normal Normal
17F candidiasis/CMC

Susceptibility to intramacrophagic pathogens

Adult-onset immunodeficiency with
AutoAb to IFN Decreased naive T cells Normal Normal (mycobacteria, fungi-Talaromyces marneffei,
susceptibility to environmental mycobacteria
Salmonella) VZV infections/MSMD, or CID
Recurrent staphylococcal skin infection AutoAb to IL-6 Normal low Normal Staphylococcal infections/STAT3 deficiency

Pulmonary alveolar proteinosis, cryptococcal meningitis,

Pulmonary alveolar proteinosis AutoAb to GM-CSF Normal Normal Normal
disseminated nocardiosis/CSF2RA deficiency

Page 70 of 79
 Acquired angioedema AutoAb to C1 inhibitor Normal Normal Normal Angioedema/C1 INH deficiency (hereditary angioedema)

AutoAb to Complement Factor aHUS = Spontaneous activation of the alternative

Atypical Hemolytic Uremic Syndrome Normal Normal Normal
H (CFH) complement pathway

Thymoma with hypogammaglobulinemia (Good AutoAb to various cytokines†

syndrome) including type I IFNs Decreased CD4+ T cells, No B cells Invasive bacterial, viral, or opportunistic infections,
Increased CD8+ T cells Decreased autoimmunity, PRCA, lichen planus, cytopenia, colitis,
chronic diarrhea
• Severe, life-threatening SARS-CoV-2 infection
• Critical / ‘breakthrough’ COVID-19 pneumonia
• adverse reactions to yellow fever YFV-17D live-
AutoAb to type 1 IFNs (IFN, attenuated viral vaccine
IFN) • critical influenza pneumonia
Critical viral infections • critical Middle East respiratory syndrome (MERS)
pneumonia
• West Nile virus (WNV) encephalitis
Sporadic infectious mononucleosis and AutoAb to IL-27 Infectious mononucleosis, chronic EBV active
chronic EBV infection infection /IL-27RA deficiency

Abbreviations for all tables

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; LOF, loss-of-function; GOF, gain-of-function; PRCA, pure red cell aplasia; Ab, antibodies; aHUS, atypical
hemolytic uremic syndrome

Total number of conditions for Table X: 17 (8 due to somatic mutations; 10 due to autoantibodies)

New phenocopies: 2, 1 due to somatic mutation in JAK193, 2 1 due to autoantibodies against IL-2763. Antibodies against type I interferons previously described for patients with Severe COVID-19 were now also
described in patients with other severe viral infections, hence this entry was modified to include SARS Co-V2 breakthrough infections as well as others116,117.
†
Autoantibodies against IL-23 were described in the context of thymoma118

Page 71 of 79
Compliance with Ethical Standards
Ethics Approval
This work is a summary of recently reported genetic variants that represent novel inborn errors of immunity. No
human research studies were performed to produce this summary. Thus, no approvals by appropriate institutional
review boards or human research ethics committees were required to undertake the preparation of this report.

Consent to Participate
Not applicable.

Consent to Publish
The authors consent to publish the content of this summary. However, as noted above, as this is a summary of
recently reported genetic variants that represent novel inborn errors of immunity, we did not require consent to
publish from participants.

Authors Contribution
IM, CP, and ST wrote the drafts of the manuscript, prepared the Table, and revised the manuscripts for
submission. All co-authors contributed to and edited drafts of manuscripts and table and approved the submitted
version.

Funding Statement
The members of the Inborn Errors of Immunity committee would like to thank the International Union of
Immunological Societies. This work was supported in part by the Intramural Research Program of the NIAID,
NIH. SGT is supported by an Investigator Grant (Level 3) awarded by the National Health and Medical Research
Council of Australia. IM is a senior clinical investigator of FWO Vlaanderen (EBD-D8974-FKM) and also
supported by Jeffrey Model Foundation. CP is supported by Regular Investigator Grant FONDECYT 1221802
and Jeffrey Modell Foundation.

Conflict of Interest
The authors declare that they have no conflict of interest.

Availability of data and materials

Not applicable

Page 72 of 79
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