Autism

Kit ID: GFX0442817

Autism
Introduction
The Autism test is based on Whole Genome Sequencing Test. As such, it analyzes all Common and Rare Variants associated with Autism instead of a limited
set of genes. Autism spectrum disorder (ASD) is a condition that appears very early in childhood development, varies in severity, and is characterized by
impaired social skills, communication problems, and repetitive behaviors. These difficulties can interfere with affected individuals' ability to function in social,
academic, and employment settings. People with ASD also have an increased risk of psychiatric problems such as anxiety, depression, obsessive-compulsive
disorder, and eating disorders. Along with environmental factors, Genetics plays a key role in the regulation of Autism. - 35 genes analyzed - 100% of
genomic regions covered - Intragenic and intergenic regions analyzed - All variants reported."

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In our analysis, we did not find any pathogenic variants.

Variants analyzed:
PTEN 1 SCN2A 2 SHANK2 1 CNTNAP2 1

Clinical Variants Found:

PTEN

10 89726659 GTTT>GT ZYG HET

rs5786797 - NM_000314.7(PTEN):c.*1457_*1459del MAF -

ACMG -
PTEN hamartoma tumor syndrome
CLIN. SIG Uncertain significance
★

SCN2A

2 166150520 T>TAA ZYG HET

rs67417831 - NM_001040142.2(SCN2A):c.-51-1736_-51-1735dup MAF -

ACMG -
Seizures
CLIN. SIG Uncertain significance
★

SCN2A

2 166150550 A>ATT ZYG HET

rs1553563950 - NM_001040142.2(SCN2A):c.-51-1721_-51-1720dup MAF -

ACMG -
Seizures
CLIN. SIG Uncertain significance
★

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SHANK2 RARE

11 70315729 A>G ZYG HET

rs78378706 - NM_012309.4(SHANK2):c.*3245T>C MAF 0.00799

ACMG -
Autism spectrum disorder
CLIN. SIG Uncertain significance
★

Informational Variants Found:

CNTNAP2
In 2 independent family-based samples, Arking et al. (2008) identified a common variant in the CNTNAP2 gene, rs7794745, that was associated with increased risk for autism (AUTS15; 612100). This
SNP resides in intron 2 of the CNTNAP2 gene. In the combined sample, overall transmission frequency of the T allele to affected children (tau = 0.55, p less than 7.35 x 10(05)) was significantly greater
from mothers (tau = 0.61) than from fathers (tau = 0.53), and this parent-of-origin difference was significant (P less than 0.001).

7 146489606 A>T ZYG HET

rs7794745 - NM_014141.6(CNTNAP2):c.208+18133A>T MAF 0.50539

ACMG -
Autism 15
CLIN. SIG Risk factor

18179894

In our analysis, we did not find any related conditions

Genes Analyzed
This report analyzed the following genes:

PTCHD1,
AUTS2,
NLGN3,
SCN2A,
CHD8,
TRRAP,
ASH1L,
SHANK2,
CNTNAP2,
SLC9A9,
TCF20,
CNOT3,
SNRPN,
ADNP,
NLGN4X,
TBR1,
GABRB3,
MECP2,
PTEN,
RPL10,
RELN,
DYRK1A,
POGZ,
SYNGAP1,
CHD2,
ARID1B,
EIF4E,
SHANK3,
TMLHE,
RERE

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Glossary

Symbol Description

Zygosity describes whether you inherited one copy of this variant from one of your parents (heterozygous), or
you inherited two copies from both of your partents (homozygous). Typically for pathogenic variants
ZYG Zygosity homozygosity cause a more severe form of the condition. In many cases, heterozygous variants do not lead to the
condition becoming apparent in the patient (also known as a recessive condition) but do mean that the next
generation is at risk of inheriting the condition (or themselves becoming a carrier).

American The American College of Medical Genetics is an organisation dedicated to the practice of medical genetics. Using a
College of series of factors related to the variant and its context, they have identified the likelihood of a specific variant being
ACMG
Medical causative for a disease. This score is based on a few factors, including allelic frequency (AF) an transcription
Genetics consequence.

Allelic frequency defines how often this variant has been observed in the general population. A very low allelic
Allelic
AF frequency could potentially be denovo (i.e. it wasn’t inherited from either of your parents). Low allelic frequency
frequency
variants are often considered more likely to be the cause of a negative phenotype or disease.

One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant
Autosomal
AD disorder. In some cases, an affected person inherits the condition from an affected parent. In others, the condition
dominant
may result from a new mutation in the gene and occur in people with no history of the disorder in their family.

In autosomal recessive inheritance, both copies of the gene in each cell have mutations. The parents of an
Autosomal individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do
AR
recessive not show signs and symptoms of the condition. Autosomal recessive disorders are typically not seen in every
generation of an affected family.

Dominant X-linked dominant disorders are caused by mutations in genes on the X chromosome, one of the two
sex chromosomes in each cell. In one of the two sex chromosomes in each cell. In females (who have two X
X-linked chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In
X-linked
dominant males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the
disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of
X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

A condition is considered Y-linked if the mutated gene that causes the disorder is located on the Y chromosome,
Y-linked Y-linked one of the two sex chromosomes in each of a male's cells. Because only males have a Y chromosome, in Y-linked
inheritance, a mutation can only be passed from father to son.

Mitochondrial inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria,
which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because
only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial
Mitochondrial Mitochondrial
mutations to their children. Conditions resulting from mutations in mitochondrial DNA can appear in every
generation of a family and can affect both males and females, but fathers do not pass these disorders to their
daughters or sons.

This variant directly contributes to the development of disease. Some pathogenic variants may not be fully
Pathogenic penetrant. In the case of recessive or X-linked conditions, a single pathogenic variant may not be sufficient to
cause disease on its own. Additional evidence is not expected to alter the classification of this variant.

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Symbol Description

There is a high likelihood (greater than 90% certainty) that this variant is disease-causing. Additional evidence is
Likely
expected to confirm this assertion of pathogenicity, but there is a small chance that new evidence may
Pathogenic
demonstrate that this variant does not have clinical significance.

Variant
VUS Uncertain There is not enough information at this time to support a more definitive classification of this variant.
significance

Phenotype Phenotype represents the observable characteristics or traits of an

organism that are produced by the interaction
Name of the genotype and the
environment : the physical expression of one or more genes.

Significance refers to the standard term used by

ClinVar, the internationally recognized database on which this
report is
based, to classify the types of variants. As the database is a clinical
database, the information is clinical
and based on an
authoritative source when available. The Significance section includes the following
standard
terms to classify the variants:

Pathogenic: A Pathogenic is classified as such if this variant

directly contributes to the development of
disease. Some pathogenic
variants may not be fully penetrant. In the case of recessive
or X-linked
conditions, a single pathogenic variant may not be sufficient to cause
disease on its own. Additional
evidence is not expected to alter the
classification of this variant.
Likely Pathogenic: A Likely Pathogenic variant is classified
as such if there is a high likelihood (greater than
90%
certainty) that
this variant is disease-causing. Additional evidence is
expected to confirm
this
Significance assertion of pathogenicity, but there is a small chance that new
evidence may demonstrate that this
variant does not have clinical
significance.
Conflicting Interpretations of Pathogenicity: A Conflicting
Interpretations of Pathogenecitity variant is
classified as
such if it is submitted from a scientific consortium, where groups within
the consortium have
conflicting interpretations of a variant but provide a single
submission to ClinVar.
Variant of Unknown Significance: A Variant of Unknown
Significance is classified as such if it is there is
not
enough information
at this time to support a more definitive classification of
this variant.
Drug response: A Drug response variant is classified as such
if it represents a complex phenotype that
emerges from the
interplay of drug-specific genetics, human body, and environmental factors.
Association: An association variant is classified as such if
there are one or more genotypes within a
population co-occur with a
phenotypic trait more often than would be expected by chance
occurrence.

ClinVar reports the level of review supporting

the assertion of clinical significance for the variation as
review status.
Stars provide a graphical representation of the aggregate
review status on web pages. Table 1 provides definitions
Review of each review status and the
corresponding number of stars. Review status is reported in
text format in ClinVar's
Status products available by FTP.
A higher number of gold stars corresponds to higher review status.
If you wish to get
more information about that, please visit
ClinVar at the following link:
https://www.ncbi.nlm.nih.gov/clinvar/docs/review_status/

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Methods
Versions

VCF Version: y2Bp2OsJPB8ppEHN81l5qjCerNIs3Rze

Clinvar Database Version: QoqCB67VTISXJBo0M_5ZtdenJ9F4gGG0

Extraction
Before sequencing, DNA extraction and library preparation processes were carried-out by automated liquid handling robots. Sequencing was completed using the NovaSeq 6000
instrument (Illumina).

The Nextera DNA Flex (Illumina) library was used during sequencing.

Analysis

Primary and secondary analysis was performed on the Illumina DRAGEN platform. Our secondary analysis extends the GATK "best practices" pipeline. This includes Variant Quality
Score Recalibration

It is important to note that applying a filter will not remove any data from the VCF file; it will just
annotate the “FILTER” column. Variants with the “PASS” annotation are
considered high quality
and may, therefore, be used for advanced downstream analysis.

Sequence data is primarily aligned to the GATK GRCh37 reference genome and mitochondria is aligned to the Revised Cambridge Reference Sequence (NC_012920.1). Additional
references may have been requested though tertiary analysis is not conducted on variant calls using references other than GRCh37.

Limitations
Test results are not interpretations. All variants reported in the genes included in the panel are reported.

Rare polymorphisms may lead to false-negative or false-positive results.

Due to limited read length and other contributing technical limitations, repeat expansions (e.g. in the Huntington gene, the SCA-genes, the myotonic dystrophy repeat region,
and other similar regions) cannot be assessed with the applied method

Disclaimer
Any preparation and processing of a sample from saliva collection kit to Dante Labs by a customer is assumed to belong to the email used by the customer at the moment of kit
registration on the Dante Labs Genome Manager platform before the shipment of the specimen to the laboratory.

The analysis and reporting conducted by Dante Labs are based on information from one or more published third-party scientific and medical studies.

Because of scientific and medical information changes over time, your risk assessment for one or more of the conditions contained within this report may also change over time.
For example, opinions differ on the importance and relative weights given to genetic factors.
Also, epidemiological data isn’t available for some conditions, and this report may not
be able to provide definitive information about the severity of a particular condition. We recommend asking your healthcare provider to correctly interpret them.
Therefore, this
report may not be 100% accurate (e.g., new research could mean different results) and may not predict actual results or outcomes.

This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). The US Food and Drug Administration (FDA) has determined that clearance or
approval of this method is not necessary and thus neither have been obtained.

Contact
Please contact [email protected] for more
information on the contents of this report, our analysis methodology, and the limitations of this process.

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Doctor's Signature
Signature Date

Report: Autism [v1.0.6, v4.2.2] 7 of 7 Kit ID: GFX0442817

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