Received: 8 May 2018 Revised: 11 June 2018 Accepted: 17 July 2018

DOI: 10.1002/ajmg.a.40504

RESEARCH REVIEW

Molecular genetics of 22q11.2 deletion syndrome

Bernice E. Morrow1 | Donna M. McDonald-McGinn2 | Beverly S. Emanuel2 |
Joris R. Vermeesch3 | Peter J. Scambler4

1
Department of Genetics, Albert Einstein
College of Medicine, Bronx, New York The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric
2
Division of Human Genetics, Children’s disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to
Hospital of Philadelphia and Department of summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to
Pediatrics, Perelman School of Medicine,
understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This
University of Pennsylvania, Philadelphia
3
mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2
Center for Human Genetics, Katholieke
Universiteit Leuven (KU Leuven), Leuven, region and the deletion is mediated by nonallelic homologous recombination events. This review
Belgium also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical
4
Institute of Child Health, University College clinical findings associated with the disorder and explain that mutations in genes on the remain-
London, London, UK ing allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the
Correspondence existence of phenotypic heterogeneity. While some patients are mildly affected, others have
Bernice E. Morrow, Department of Genetics,
Albert Einstein College of Medicine, 1301
severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the
Morris Park Avenue, Bronx, NY 10461. presence of genetic modifiers. This review discusses current genome-wide efforts to identify
Email: [email protected] such modifiers that could shed light on molecular pathways required for normal human develop-
Funding information ment, cognition or behavior.
British Heart Foundation, Grant/Award
Numbers: PG/09/065/27893 ,
PG/09/065/27893; Fondation Jérôme KEYWORDS
Lejeune, Grant/Award Number: #1665; 22q11.2 deletion syndrome, chromosome rearrangements, congenital malformation, birth
Foundation Leducq; National Heart, Lung, and
defect syndrome, pharyngeal apparatus, DiGeorge syndrome, velo-cardio-facial syndrome
Blood Institute, Grant/Award Number:
HL132577; National Institute of Child Health
and Human Development, Grant/Award
Number: HD070454; National Institute of
Mental Health, Grant/Award Number:
MH087636MH101720

1 | C L I N I C A L A S P E C T S OF 22 Q 1 1 . 2 individuals have mild to serious medical features including most often

D E LE T I O N S Y N D RO M E congenital heart disease, immunodeficiency, autoimmune disease, pal-
atal abnormalities, hypocalcemia (often associated with hypoparathy-
The chromosome 22q11.2 region is susceptible to meiotic chromo- roidism), thyroid disease, gastrointestinal differences, renal anomalies,
some rearrangements leading to congenital malformation syndromes. skeletal anomalies, thrombocytopenia, and characteristic facial fea-
The best characterized among these is the 22q11.2 deletion syndrome tures (Bassett et al., 2011; McDonald-McGinn et al., 2015). The major-
(22q11.2DS; velo-cardio-facial syndrome (MIM#192430) or DiGeorge ity has deficits in cognitive abilities and 25% develop schizophrenia
syndrome (MIM#188400). The disorder is the most common among (Bassett & Chow, 1999; Murphy, Jones, & Owen, 1999). Other signifi-
microdeletion syndromes, occurring in ~1/4000 live births (Botto cant behavioral anomalies occur including attention deficit disorder
et al., 2003; Devriendt, Fryns, Mortier, van Thienen, & Keymolen, and anxiety (Biswas & Furniss, 2016; Campbell, McCabe, Melville,
1998; Goodship, Cross, LiLing, & Wren, 1998), and 1/1,000 fetuses Strutt, & Schall, 2015; Niarchou, Martin, Thapar, Owen, & van den
(Grati et al., 2015; Wapner et al., 2012). It occurs as a de novo 1.5–3 Bree, 2015; Vangkilde et al., 2016; Vorstman et al., 2015). Further
million base pair (Mb) deletion in most individuals (Lindsay et al., medical and psychiatric disorders occur less often in affected individ-
1995; Morrow et al., 1995), although approximately 5% are inherited uals but at higher frequencies than the general population (Bassett
(McDonald-McGinn et al., 2001). When inherited, there is a 50% et al., 2011; McDonald-McGinn et al., 2015; Ritter et al., 2015). Most
recurrence risk with 100% penetrance and wide expressivity. Affected recently, adult patients with 22q11.2DS have developed Parkinson’s

2070 © 2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ajmg Am J Med Genet. 2018;176A:2070–2081.

MORROW ET AL. 2071

disease (Boot et al., 2018; Butcher et al., 2013; Rehman, Dhamija, the LCR22s and surrounding regions might be elucidated. This will
Williams, & Barrett, 2015). This is a newly appreciated complication in provide enhanced insight into the mechanisms responsible for the
association with 22q11.2DS. Studies of the condition provide deletion and its associated phenotypes. Further, it will likely provide
opportunities to dissect out genetic and environmental risk factors or an approach to deletion breakpoint detection in a clinical setting.
modifiers within the 22q11.2 region and elsewhere in the genome. As
the condition results from the deletion, it is necessary to understand
why the deletion occurs.
4 | C L I N I C A L T E S TI N G F O R T H E 2 2 Q 1 1 . 2
DELETION

2 | M E C H A N I S M F O R M E I O T I C 22 Q 1 1 . 2 There are several different molecular tools that have been developed
C HR OM OSOM E R E A R RA N G E M E NT S for clinical purposes to identify the 22q11.2 deletion. Classic testing
by fluorescence in situ hybridization (FISH) utilizes commercial probes
The 22q11.2 deletion usually occurs by meiotic nonallelic homologous such has N25 or TUPLE (Figure 1). The two FISH probes map to the
recombination (NAHR) events between low copy repeats on chromo- LCR22A-B region, thus the probes will identify typical deletions, but
some 22q11.2 termed LCR22 (Edelmann, Pandita, & Morrow, 1999a; would miss atypical nested deletions that occur outside the A-B
Edelmann, Pandita, Spiteri, et al., 1999b; Shaikh et al., 2000). Low region. Multiplex Ligation-dependent Probe Amplification (MLPA) has
copy repeats are also referred to as segmental duplications (Bailey probes that are spaced throughout the 22q11.2 region and can be
et al., 2002). There are eight LCR22s that span the 22q11.2 region used to identify typical and atypical deletions (Fernandez et al., 2005;
termed LCR22A through LCR22H. There are four LCR22s that map to Vorstman et al., 2006). MLPA is most useful to confirm a suspected
the 3 Mb region associated with the disorder and they are termed diagnosis because it only probes the 22q11.2 region. Clinical
LCR22A, LCR22B, LCR22C, and LCR22D. In over 90% of patients, the genome-wide microarray testing (single nucleotide polymorphism/
region between LCR22A-D is hemizygously deleted. This is referred SNP genotyping microarray or microarray comparative genome
to as the LCR22A-D deletion type. The 1.5 Mb deletion between hybridization-CGH) is useful when it is not possible to make a definitive
LCR22A-B is the second most common deletion type, while the diagnosis based upon clinical presentation or when MLPA is not clini-
2.0 Mb LCRA-C deletion is least frequent ([Carlson et al., 1997]; cally available. One of the unexpected discoveries of genome-wide
Figure 1). LCR22A and LCR22D are the largest in size and have the testing is the expansion of the known phenotypic spectrum in patients
most homology to each other, making them good targets for NAHR with 22q11.2DS. Further, it has identified atypical nested 22q11.2 dele-
events. The LCR22s are composed of modules harboring pseudogenes tions such as the LCR22B-D or C-D deletions. These patients have
that formed during primate evolution by the processes of gene dupli- some related features to those with the typical deletions, but they
cation and gene conversion events (Babcock et al., 2003; Babcock occur with reduced penetrance (Racedo et al., 2015; Rump et al., 2014).
et al., 2007; Pavlicek, House, Gentles, Jurka, & Morrow, 2005). Each What is truly fascinating is that the LCR22A-B deleted region does not
LCR22 is a complex mosaic of modules that has been challenging to overlap with the LCR22B-D or C-D region, ascribing haploinsufficiency
precisely map in humans. This complexity has made it exceedingly of different genes to some similar phenotypes. The extent of the simi-
difficult to identify the position of chromosome breakpoints in deleted larity of phenotypes should be taken with a word of caution because
patients (Guo et al., 2016; Guo et al., 2011). more patients with less frequently occurring deletions need to be ana-
lyzed to fully appreciate the range or severity of anomalies. The exis-
tence of atypical deletions underscores the importance of evaluating
3 | E F FO R T S T O D ET E RM I N E T H E 2 2 Q 1 1 . 2 deletion size as well as of understanding the function of genes through-
D E LE T I O N E ND P O I N T S out the 22q11.2 region to delineate their role in individual abnormali-
ties and the overall phenotype of the disorder.
There has been much interest to clone and sequence the position
of the chromosome 22q11.2 breakpoints leading to the typical
LCR22A-D deletion. Due to the complexity of LCR22 structure, usage 5 | G E N E S ON 22 Q 1 1 . 2 TH A T C A U S E
of traditional sequencing methods has only been partially successful, CONGENITAL MALFORMATIONS
as eluded to above (Guo et al., 2016). This technical challenge can
potentially be alleviated by the application of optical genome mapping There are 45 known protein coding genes, seven miRNA and 10 non-
techniques. One approach utilizes long single molecules imaged in coding genes that map to the 3 Mb, 22q11.2 region, as well as addi-
nanochannel arrays to generate molecular maps (Lam et al., 2012; tional predicted coding and non-coding genes as shown in Figure 1.
Mak et al., 2016). Another approach is molecular combing with tar- Among the genes mapping to the LCR22A-B region is TBX1, which
geted probes flanking and targeting the LCR22 subunits, which will encodes a T-box type of transcription factor. This gene has received
visualize the probe patterns along DNA fibers. The stretching of chro- much attention for a major role in medical aspects of the disorder.
matin is a particular process needed to form the fibers (Michalet et al., Heterozygous mutations within TBX1 have been identified in patients
1997). By leveraging the increased sensitivity afforded by long single with similar defects as occurs in those with 22q11.2DS (Castellanos,
molecule optical maps, coupled with low coverage whole-genome Xie, Zheng, Cvekl, & Morrow, 2014; Gong et al., 2001; Griffin et al.,
sequence, the previously unmappable architecture and variation of 2010; Ogata et al., 2014; Pan et al., 2015; Stoller & Epstein, 2005;
2072 MORROW ET AL.

FIGURE 1 The 22q11.2 region. This image was modified from a previously published image (McDonald-McGinn et al., 2015). The 3 Mb 22q11.2
region (hg19 assembly, coordinates) is shown as a line that spans the 22q11.2 region, distal to the centromere (Cen) and harbors four sets of low
copy repeats (LCR22), termed LCR22A, LCR22B, LCR22C and LCR22D (gray boxes). The position of clinical diagnostic probes, N25 and TUPLE,
for clinical fluorescence in situ hybridization (FISH) testing are shown (green boxes). Most of the known coding and noncoding genes that span
the interval are shown below the line representing the 22q11.2 region. TBX1 is indicated in blue font. Genes associated with recessive genetic
conditions are indicated in red font. Noncoding genes are indicated with a star. The size and position of 22q11.2 deletions are indicated (gray
boxes). The frequencies of deletions were obtained from McDonald-McGinn and colleagues in the special AJMG issue [Color figure can be
viewed at wileyonlinelibrary.com]

Torres-Juan et al., 2007; Xu et al., 2014; Yagi et al., 2003; Zweier, In mammals, Tbx1 is expressed in the embryonic cells that will form
Sticht, Aydin-Yaylagul, Campbell, & Rauch, 2007). Supporting this, and the craniofacial region, thymus and parathyroid glands, aortic arch as
occurring chronologically before mutations in patients were discov- well as cardiac outflow tract. These are the structures affected in
ered, mouse models in which Tbx1 was inactivated were generated 22q11.2DS and in Tbx1 loss of function mouse embryos. The Tbx1
(Jerome & Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., expressing cells lie within the embryonic pharyngeal apparatus
2001). Inactivation of one allele resulted in mild cardiovascular (Figure 2), which is a structure that will form gills in fish but becomes
defects, but inactivation of both alleles resulted in cleft palate, thymic, dramatically remodeled in mammals. Tbx1 is expressed and functions in
and parathyroid gland aplasia as well as cardiovascular defects all three germ layers of the pharyngeal apparatus, namely the endoderm
(Jerome & Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., (Arnold et al., 2006; Jackson, Kasah, Mansour, Morrow, & Basson,
2001). A series of alleles was generated with varying expression levels 2014; Zhang et al., 2005), mesoderm (Zhang, Huynh, & Baldini, 2006),
of Tbx1 and it was found that the gene is very sensitive to changes in and ectoderm (Zhang et al., 2005). These cells communicate signals to
copy number, such as what occurs when one allele is deleted in neural crest cells. Neural crest cells comprise a population of cells that
humans (Baldini, 2006; Zhang & Baldini, 2008). Of interest, it was dis- delaminates and migrates from the neural tube. These cells make a
covered that different tissues and organs have different degrees of major contribution to morphogenesis of the structures affected in
sensitivity to Tbx1 dosage and suggests that altered regulation of its 22q11.2DS (Calmont et al., 2009). This illustrates the complexity of the
expression could explain phenotypic variability in patients (Zhang & tissue interactions that are required for morphogenesis of the deriva-
Baldini, 2008). Further, overexpression of human or mouse Tbx1 is tive structures from the pharyngeal apparatus (Papangeli & Scambler,
able to genetically rescue malformations that occur in mouse deletion 2013). Recently, direct downstream transcriptional target genes of
models equivalent to the LCR22A-B deletion (Lindsay et al., 2001; TBX1 protein were discovered and a link to chromatin modification in
Merscher et al., 2001). The discovery of TBX1 as a major player in connection with TBX1 was identified (Baldini, Fulcoli, & Illingworth,
medical aspects of 22q11.2DS has allowed the exploration of genetic 2017; Fulcoli et al., 2016). This work has led to the hypothesis that inhi-
pathways upstream and downstream of TBX1 needed for normal bition of histone demethylases might rescue the CHD phenotype in
embryonic development (Ivins et al., 2005; Liao et al., 2008). Tbx1 loss of function embryos (Baldini et al., 2017; Fulcoli et al., 2016).
MORROW ET AL. 2073

miRNA genes that map to the 22q11.2 region (Figure 1) and they have
not been studied in detail, as of yet. Another potentially relevant gene
is HIC2 (Hypermethylated in Cancer 2). HIC2 maps to a small unique
genomic region near the distal end of LCR22D and it is not usually
deleted in patients. However, some individuals have atypical longer
deletions in LCR22D that extend beyond HIC2 (Dykes et al., 2014).
HIRA is also of interest, because it encodes a component of a protein
complex that deposits the variant histone H3.3 at regulatory regions
of genes, thereby modulating gene expression (Dilg et al., 2016; Farrell
et al., 1999; Majumder, Syed, Joseph, Scambler, & Dutta, 2015; Zhang
et al., 2017). Supporting a possible relevant function, conditional inac-
tivation of Hira in mouse mesoderm cells causes cardiac defects
FIGURE 2 Embryonic development of the pharyngeal apparatus into (Manchineella, Thrivikraman, Basu, & Govindaraju, 2016).
adult structures. Cartoon of a lateral view of a mouse embryo at stage
day (E) 10.5 in development. The head is shown on top and the tail
can be visualized as it twists around the body of the embryo. The 6 | G E N E S ON 22 Q 1 1 . 2 TH A T A F F E C T T H E
pharyngeal apparatus is highlighted in light blue with individual arches
B R A I N OR BE H A V I O R
(PA) and their derivative structures indicated on the left side (arrows).
The outflow tract (OFT), right ventricle (RV), forelimb (FL), and
hindlimb (HL) are indicated. Cells migrate from the pharyngeal The relative importance of individual genes on chromosome 22q11.2
apparatus into the cardiac OFT to form the aorta and pulmonary trunk that contribute to cognitive and behavioral problems in patients is still
during later stages of embryogenesis [Color figure can be viewed at being elucidated. Genes in the nested, LCR22A-B region have been
wileyonlinelibrary.com]
more extensively evaluated than those in the distal, LCR22B-D region.
The LCR22A-B region was identified as the smallest region of overlap
Besides TBX1, there is another gene that may contribute to the
between deletion types in 22q11.2DS patients presenting with the
medical findings in 22q11.2DS and the gene is termed CRKL (CRK like
typical manifestations of 22q11.2DS, including schizophrenia
proto-oncogene, adaptor protein). CRKL maps to the LCR22C-D region
(Karayiorgou et al., 1995). Patients with LCR22B-D or C-D deletions
and it encodes a cytoplasmic adaptor protein involved in growth factor
have only been identified recently due to the clinical utilization of
signaling. Crkl is required for development of the thymus and parathy-
microarrays for genetic testing. Because of the smaller number that
roid glands, aortic arch, and heart (Guris, Duester, Papaioannou, &
have been characterized, it is not known whether schizophrenia is an
Imamoto, 2006; Guris, Fantes, Tara, Druker, & Imamoto, 2001; Moon
important feature in such patients. Identifying which gene(s) contrib-
et al., 2006). Of interest, inactivation of both alleles of Crkl in the mouse
ute to these anomalies has been challenging because the great major-
results in similar defects as in Tbx1 null mutant mice. Mice that have
ity of genes in the LCR22A-B region are expressed in the brain
one allele of Tbx1 and Crkl inactivated together have similar defects as
in 22q11.2DS patients (Guris et al., 2006; Guris et al., 2001). This sup- (Maynard et al., 2003). In humans, the gene most well-studied for such

ports the idea that the two genes act in the same genetic pathway. deficits is COMT (Catechol-O-methyltransferase). The COMT protein

Unlike Tbx1, whose expression is restricted in specific cells and tissues, has a critical role in dopamine neurotransmitter metabolism. Further,

Crkl is ubiquitously expressed in all cells (Guris et al., 2001). It is hypoth- there is a commonly occurring coding variant, referred to as Val158-

esized that Tbx1 acts upstream of the Fgf8 (Fibroblast growth factor 8) Met that affects enzyme activity (Li et al., 1996). While some studies

growth factor gene, and this activates CRKL in neural crest cells and support a role of reduced enzyme activity of COMT to cause cognitive

leads to activation of downstream signaling (Moon et al., 2006). and/or behavioral deficits, others do not, and the importance of this
Recently, it was found that hemizygosity of CRKL contributes to genito- functional variation in COMT remains controversial (Armando,
urinary tract development in humans and animal models, including the Papaleo, & Vicari, 2012; Franconi et al., 2016). Another gene that has
kidney (Haller, Mo, Imamoto, & Lamb, 2017; Lopez-Rivera et al., 2017). been extensively studied in humans is PRODH, encoding proline dehy-
Although these are not considered the most common of defects in drogenase that converts proline to glutamate, involved in neurotrans-
22q11.2DS, they occur more commonly than the general population. mission. As is true for COMT, the role of PRODH is not yet definitive
Besides coding genes, non-coding genes, such as miRNAs might also (Carmel et al., 2014; Radoeva et al., 2014; Zarchi et al., 2013).
contribute to the etiology of 22q11.2DS. Commonly occurring single nucleotide polymorphisms in additional
The miRNAs are small noncoding RNAs that regulate expression genes have been identified in patients with schizophrenia, but most of
of target genes by binding to specific sites in messenger RNAs causing the studies were small in size and some of the findings failed replica-
repression of translation or degradation. Another gene of note tion. Another gene worth mentioning is PIK4CA. This gene encodes
required for both cardiovascular and brain development or function is Phosphatidylinositol 4-kinase alpha and has been considered a candi-
DGCR8 (DiGeorge Critical Region 8; [Chapnik, Sasson, Blelloch, & date for schizophrenia, although this possibility remains controversial
Hornstein, 2012; Earls et al., 2012; Sellier et al., 2014]). This gene (Ikeda et al., 2010; Vorstman et al., 2009). Further, the gene maps out-
encodes a subunit of a microprocessor complex that mediates the bio- side the LCR22A-B region, considered to be the critical region for
genesis of miRNAs (Gregory et al., 2004). Further, there are several schizophrenia on 22q11.2. More studies need to be done on patients
2074 MORROW ET AL.

with LCR22B-D or LCR22C-D deletions to understand the function of These findings of recessive disorders and a possible somatic dom-
genes in this region as risk factors for schizophrenia. inant condition, confirm that extreme phenotypic abnormalities
Genes in the LCR22A-B region have been carefully evaluated in observed in a subset of patients with 22q11.2DS can be due to muta-
mouse models for a possible role in brain development or function tions on the nondeleted allele, leading to unmasking of additional con-
(Karayiorgou & Gogos, 2004; Wang, Bryan, LaMantia, & Mendelowitz, ditions. It is also possible that less severe mutations or variations on
2017). Genes of interest required for brain or behavioral function in the remaining allele could contribute to phenotypic variability in
mouse models are Zdhhc8 (Zinc finger DHHC-type containing 8; 22q11.2DS. On the other hand, recessive mutations in essential genes
[Mukai et al., 2004]), Ranbp1 (Ran GTPase-binding protein; (Paronett, would likely cause early embryonic lethality, in which we would not
Meechan, Karpinski, LaMantia, & Maynard, 2015), Rtn4r (Reticulon be able to identify in the human population.
4 receptor; NOGOR; [Hsu et al., 2007; Kimura et al., 2017]), and Dgcr8
(Diamantopoulou et al., 2017; Eom, Bayazitov, Anderson, Yu, &
Zakharenko, 2017; Fenelon et al., 2011; Stark et al., 2008). Genes 8 | PHENOTYPIC VARIABILITY AND
important for mitochondrial function are newly appreciated in mouse
2 2Q 11 . 2 D S
models, to have a role in the etiology of schizophrenia (Devaraju &
One of the most challenging features of 22q11.2DS is its phenotypic
Zakharenko, 2017; Meechan, Maynard, Tucker, & LaMantia, 2011),
variability, despite the fact that most patients have the same size,
and specifically, for example, Mrpl40 [Mitochondrial large ribosomal
3 Mb deletion. For example, 60%–70% have congenital heart disease,
subunit protein 40; (Devaraju et al., 2017)]. Further work needs to be
which includes many different aortic arch and/or cardiac outflow tract
done to understand the relative importance of these genes in humans.
anomalies (Goldmuntz et al., 1993; McDonald-McGinn et al., 2015;
Swillen & McDonald-McGinn, 2015). Other common features include
7 | UNCOVERING OF RECESSIVE cleft of the muscular palate/velopharyngeal dysfunction, endocrine
M U T A T I O N S ON 22 Q 1 1 . 2 abnormalities including hypocalcemia, thyroid disease, and growth
hormone deficiency, immunodeficiency/autoimmune disease, gastro-
Over the years, some subjects have been identified with unusual clini- enterological issues, skeletal abnormalities such as scoliosis, as well as,
cal findings cooccurring with the main phenotypes of 22q11.2DS. neuropsychiatric and cognitive deficits. As mentioned above, schizo-
One possible explanation is that there is a mutation in a gene on the phrenia occurs in 25% of individuals with the disorder (Bassett &
remaining, haploid allele of 22q11.2 resulting in the co-occurrence of Chow, 1999; Murphy et al., 1999). Analysis of 21,094 cases with
a recessive disorder. This explanation is exactly what has been found schizophrenia and 20,227 controls without psychiatric disease identi-
to occur in some patients with 22q11.2DS that also have atypical phe- fied the 22q11.2 deletion as the most significantly associated copy
notypes. Several genes within the deleted region have been identified number variation (Marshall et al., 2017). The 22q11.2 deletion is the
as harboring autosomal recessive mutations and they are listed in most common pathogenic copy number variations associated with
Table 1. Five genes, PRODH (Afenjar et al., 2007; Bender et al., 2005; schizophrenia. Despite this, most patients with 22q11.2DS do not
Efron, 1965; Goodman, Rutberg, Lin, Pulver, & Thomas, 2000; Jacquet develop schizophrenia.
et al., 2002, 2003), SLC25A1 [Solute family carrier 25 member One possible explanation for altered phenotypic expression of
1 (Edvardson et al., 2013; Majd, King, Smith, & Kunji, 2018; Nota medical and behavioral disorders, is the existence of other genetic var-
et al., 2013)], CDC45 [Cell division cycle 45; (Fenwick et al., 2016)], iations in the genome, in addition to the deletion that act as modifiers.
GP1BB [Glycoprotein 1b platelet subunit beta; (Budarf et al., 1995; Another possible explanation is the occurrence of stochastic events
Hayashi & Suzuki, 2000; Kato et al., 2003; Kunishima et al., 2013; during embryogenesis and a third is the existence of as of yet,
Lawrence, McDonald-McGinn, Zackai, & Sullivan, 2003; Ludlow et al., unknown environmental exposures in pregnancy. Of interest, mono-
1996; Roth, 1996; Tang et al., 2004)] and AJMGAGO2 [Transport and zygotic twins with 22q11.2DS typically have discordant features
golgi organization 2 homolog; (Kremer et al., 2016; Lalani et al., (Fryer, 1996; Goodship, Cross, Scambler, & Burn, 1995; Halder, Jain,
2016)], map to the LCR22A-B region. In addition to mutations occur- Chaudhary, & Varma, 2012; Hatchwell, 1996; Lu, Chung, Hwang, &
ring on the other allele in 22q11.2DS patients, other patients have Chien, 2001; McDonald-McGinn et al., 2001; Rauch et al., 1998;
been reported to have point mutations on both alleles but do not Singh, Murphy, & O’Reilly, 2002; Vincent et al., 1999; Yamagishi et al.,
carry the deletion (Table 1). Each recessive disorder has individual 1998). This implicates stochastic events, epigenetic variation in preg-
characteristic clinical findings as listed in Table 1. SCARF2 [Scavenger nancy or somatic mutations as also contributing to variation.
receptor class F member 2; (Bedeschi et al., 2010)] maps to the Among the possibilities, identifying genetic modifiers on the
LCR22B-C region, while SNAP29 [Synaptosome associated protein remaining 22q11.2 allele or elsewhere in the genome are feasible to
29; (Hsu et al., 2017; McDonald-McGinn et al., 2013; Sprecher et al., test in sufficient sized cohorts of affected individuals. This may be
2005)] maps to the LCR22C-D region. Separate from these birth useful for identifying modifiers of congenital heart disease because
defect syndromes, somatic loss of heterozygosity of one allele and a this phenotype is usually available for patients and it is identified soon
loss of function mutation in LZTR1 on the other allele predispose indi- after birth. For this, first, mutations in the coding region of TBX1 were
viduals to an inherited disorder of multiple schwannomas (Piotrowski ruled out as factors that influence cardiovascular phenotypes in a
et al., 2014). large cohort of 22q11.2DS patients (Guo et al., 2011).
 MORROW ET AL.

TABLE 1 Recessive mutations in genes on the 22q11.2 region

22q11.2DS +
Gene name Map position (hg19 assembly) Disease name MIM # mutation Phenotype PMID
PRODH A-B; (chr22:18,900,287-18,924,066) Hyperprolinemia type 1 239500 YES Neurological deficits, psychomotor delay, hypotonia, 11196113; 12217952; 12525555;
and seizures. 14290545; 15662599;
17412540
SLC25A1 A-B (chr22:19,163,088-19,166,338) D2L2AD syndrome 615182 YES Encephalopathy, severe muscular weakness, seizures, 23393310, 23561848, 29031613
respiratory distress, failed psychomotor
development, early death
CDC45 A-B (chr22:19,467,414-19,508,135) Meier-Gorlin syndrome 7 617063 NO Craniosynostosis, imperforate anus, limb abnormalities, 27374770
short stature, absent patellae, and microtia
GP1BB A-B; (chr22:19,705,992-19,712,297) Bernard-Soulier syndrome 231200 YES Hematologic disease; thrombocytopenia; increased 8952885; 10805283; 23566026
megakaryocytes
AJMGAGO2 A-B (chr22:20,008,631-20,053,447) MECRCN syndrome 616878 NO Recurrent metabolic crises with 26805781; 26805782
encephalocardiomyopathy that includes
rhabdomyolysis, neurodegeneration, hearing loss,
thyroid disease, hypoglycemia, seizures, dystonia,
and sudden death
SCARF2 B-C (chr22:20,778,874-20,792,146) van den Ende-Gupta syndrome 600920 YES Contractual arachnodactyly, hooked clavicles, joint 22140376
dislocations, and blepharophimosis
SNAP29 C-D (chr22:21,213,292-21,245,501) CEDNIK syndrome 609528 YES Cerebral dysgenesis, neuropathy, ichthyosis, and 15968592; 23231787; 29051910
keratoderma

Each gene is listed with respect to the map location and to the position of the LCR22s. The genomic coordinates in the hg19 genome assembly is listed in the second column. The name of the genetic syndrome caused
by recessive mutations is listed as is the Online Mendelian Inheritance in Man (MIM) number. Characteristic clinical features of each disorder are shown. The references used to create the table are listed by PMID
(PubMed ID) in the column on the right and are cited in the text.
2075
2076 MORROW ET AL.

In terms of genetic factors, one obvious category to investigate is CON F L I C T S OF IN TE RE S T

the presence of second-hit large-sized copy number variations We have no conflicts of interest to declare.
(CNVs). The CNVs might contain genes whose function is sensitive to
copy number for various phenotypes. Some may act in the same ORCID
genetic pathway as 22q11.2 genes, and either exacerbate or suppress
Bernice E. Morrow https://orcid.org/0000-0002-8076-4726
individual phenotypes. Affymetrix 6.0 arrays on almost 1,000 subjects
with 22q11.2DS revealed a commonly occurring duplication CNV
containing the SLC2A3 (Solute carrier family 3 member 2) gene in indi- RE FE RE NC ES
viduals with 22q11.2DS with congenital heart disease compared to Afenjar, A., Moutard, M. L., Doummar, D., Guet, A., Rabier, D.,
Vermersch, A. I., … Rodriguez, D. (2007). Early neurological phenotype
those with the condition but with normal cardiac and/or aortic arch
in 4 children with biallelic PRODH mutations. Brain Dev, 29(9),
structures (Mlynarski et al., 2015). Analysis of rare CNVs that alter risk 547–552. https://doi.org/10.1016/j.braindev.2007.01.008
to cardiovascular anomalies has been more challenging, with no spe- Armando, M., Papaleo, F., & Vicari, S. (2012). COMT implication in cogni-
cific increased burden of CNVs, but it is possible, when taken together tive and psychiatric symptoms in chromosome 22q11 microdeletion
syndrome: A selective review. CNS & Neurological Disorders Drug Tar-
that CNVs harboring genes important for cardiovascular development
gets, 11(3), 273–281.
play a role in this sensitized population (Mlynarski et al., 2016). Arnold, J. S., Werling, U., Braunstein, E. M., Liao, J., Nowotschin, S.,
Recently, rare CNVs were shown to contribute to schizophrenia and Edelmann, W., … Morrow, B. E. (2006). Inactivation of Tbx1 in the pha-
ryngeal endoderm results in 22q11DS malformations. Development,
22q11.2DS (Bassett et al., 2017).
133(5), 977–987. https://doi.org/10.1242/dev.02264
Whole exome sequencing on 184 individuals with 22q11DS, in Babcock, M., Pavlicek, A., Spiteri, E., Kashork, C. D., Ioshikhes, I.,
which roughly half had severe cardiac anomalies and half had no Shaffer, L. G., … Morrow, B. E. (2003). Shuffling of genes within
defect, identified genes important for chromatin modification as low-copy repeats on 22q11 (LCR22) by Alu-mediated recombination
events during evolution. Genome Research, 13(12), 2519–2532.
altering risk (Guo et al., 2015) as well as additional genes with rare
https://doi.org/10.1101/gr.1549503
possible damaging variants, for cardiac development (Lin, Zhang, Cai, Babcock, M., Yatsenko, S., Hopkins, J., Brenton, M., Cao, Q., de Jong, P., …
Morrow, & Zhang, 2017). Examination of whole genome sequence Morrow, B. E. (2007). Hominoid lineage specific amplification of
low-copy repeats on 22q11.2 (LCR22s) associated with
(WGS) in >1,500 subjects with 22q11.2DS is currently underway to
velo-cardio-facial/digeorge syndrome. Human Molecular Genetics,
identify genetic factors for congenital heart disease as well as for 16(21), 2560–2571. https://doi.org/10.1093/hmg/ddm197
schizophrenia (Gur et al., 2017). The availability of WGS will enable Bailey, J. A., Yavor, A. M., Viggiano, L., Misceo, D., Horvath, J. E.,
scientists to identify common and rare single nucleotide variations in Archidiacono, N., … Eichler, E. E. (2002). Human-specific duplication
and mosaic transcripts: The recent paralogous structure of chromo-
coding and noncoding regions, as well as large or smaller second-hit some 22. American Journal of Human Genetics, 70(1), 83–100. https://
CNVs that serve as modifiers. It can be hypothesized that some of the doi.org/10.1086/338458
genes or regulatory regions that will be uncovered likely interact with Baldini, A. (2006). The 22q11.2 deletion syndrome: A gene dosage per-
spective. ScientificWorldJournal, 6, 1881–1887. https://doi.org/10.
genes that are hemizygously deleted on the 22q11.2 region.
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Baldini, A., Fulcoli, F. G., & Illingworth, E. (2017). Tbx1: Transcriptional and
developmental functions. Current Topics in Developmental Biology, 122,
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Bassett, A. S., & Chow, E. W. (1999). 22q11 deletion syndrome: A genetic
subtype of schizophrenia. Biological Psychiatry, 46(7), 882–891.
Following the discovery of the 22q11.2 deletion in patients, almost
Bassett, A. S., Lowther, C., Merico, D., Costain, G., Chow, E. W. C., van
40 years ago, there is still much to learn about molecular aspects of Amelsvoort, T., … Behavior, C. (2017). Rare genome-wide copy number
the condition. This includes efforts to determine the mechanism variation and expression of schizophrenia in 22q11.2 deletion syn-
drome. The American Journal of Psychiatry, 174(11), 1054–1063.
of chromosome 22q11.2 deletions that could lead to development of
https://doi.org/10.1176/appi.ajp.2017.16121417
improved clinical screening methods and understanding the genes Bassett, A. S., McDonald-McGinn, D. M., Devriendt, K., Digilio, M. C.,
responsible for typical as well as atypical phenotypes. Further, Goldenberg, P., Habel, A., … International 22q11.2 Deletion Syndrome
22q11.2DS serves as a model to understand how genetics and the Consortium. (2011). Practical guidelines for managing patients with
22q11.2 deletion syndrome. The Journal of Pediatrics, 159(2), 332–339.
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ACKNOWLEDGMENTS 22q11.12 de novo deletion in a patient with van den Ende-Gupta syn-
drome. Molecular Syndromology, 1(5), 239–245. https://doi.org/10.
We would like to thank the families with 22q11.2DS who have partic- 1159/000328135
ipated in molecular genetic studies. This work was supported by Bender, H. U., Almashanu, S., Steel, G., Hu, C. A., Lin, W. W., Willis, A., …
grants NIH R01 HL084410 (BSE, BEM, DMM), P01 HD070454 (BSE, Valle, D. (2005). Functional consequences of PRODH missense muta-
tions. American Journal of Human Genetics, 76(3), 409–420. https://doi.
BEM, DMM), MH087636 (BSE, DMM), U01 MH101720 (BSE, DMM,
org/10.1086/428142
JV), R01 HL132577 (BEM), and a Foundation Leducq grant (BEM, Biswas, A. B., & Furniss, F. (2016). Cognitive phenotype and psychiatric
PJS). This work was also funded by the British Heart Foundation, disorder in 22q11.2 deletion syndrome: A review. Research in Develop-
mental Disabilities, 53-54, 242–257. https://doi.org/10.1016/j.ridd.
PG/09/065/27893 (PJS). This work was made possible by grants from
2016.02.010
the KUL PFV/10/016 SymBioSys, GOA/12/015 G.0E1117N, the Boot, E., Butcher, N. J., Udow, S., Marras, C., Mok, K. Y., Kaneko, S., …
Jerome Lejeune Foundation (project #1665) to JRV. International Research Group on 22q11.2DS-associated Parkinson's
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