NEURODEVELOPMENT NEXT-GENERATION SEQUENCING PANELS

(1)

NEURODEVELOPMENT NEXT-GENERATION

SEQUENCING PANELS

(2)

(3)

(4)

GENETIC TESTING FOR NEURODEVELOPMENTAL DISEASE

5 G

ENETICS

5 I

NDICATIONS

5 T

ESTING

M

ETHODS

,

S

ENSITIVITY

,

AND

L

IMITATIONS

6 T

URNAROUND

T

IME

8 S

PECIMEN AND

S

HIPPING

R

EQUIREMENTS

8 C

USTOMER

S

ERVICES AND

G

ENETIC

C

OUNSELING

9 THE COMPREHENSIVE EPILEPSY AND AUTISM PANEL

10 THE COMPREHENSIVE EPILEPSY PANEL

32 FOCAL, GENERALIZED, AND MYOCLONIC EPILEPSY SUBPANEL

48 INFANTILE EPILEPSY SUBPANEL

52 MIGRAINE SUBPANEL

56 NEURONAL CEROID LIPOFUSCINOSES SUBPANEL

57 NEURONAL MIGRATION SUBPANEL

58 SYNDROMIC EPILEPSY AND INTELLECTUAL DISABILITY SUBPANEL

61 THE COMPREHENSIVE AUTISM SPECTRUM DISORDER PANEL

67 STAT AUTISM SPECTRUM DISORDER SUBPANEL

80 MICROCEPHALY PANEL

84 REFERENCES

89

(5)

Genetic Testing for

NEURODEVELOPMENTAL DISEASE

Sema4 offers targeted next-generation sequencing (NGS) for neurodevelopmental conditions such as autism spectrum

disorder, Intellectual disability, epilepsy, seizures, brain malformations, and microcephaly. NGS technology is ideal for

diagnostic testing of these disorders due to the extreme locus heterogeneity and phenotypic overlap of the genes involved.

Our customizable targeted NGS panel uses Agilent SureSelect

TM

_{QXT target enrichment and Illumina NovaSeq sequencing}

to detect pathogenic variants in genes involved in neurodevelopmental disease. Sema4 offers three primary

neurodevelopmental panels: 1) the Comprehensive Epilepsy and Autism Panel (401 genes); and 2) the Microcephaly Panel

(78). The Comprehensive Epilepsy and Autism Panel includes the Comprehensive Autism Spectrum Disorder (ASD) Panel

(228) and the Comprehensive Epilepsy (226) panels. The Comprehensive Autism Spectrum Disorder Panel includes the

STAT Autism Panel (30 genes). The Comprehensive Epilepsy Panel includes the Focal, Generalized, and Myoclonic Epilepsy

(52), Infantile Epilepsy (58), Migraine (7), Neuronal Migration (22), Neuronal Ceroid Lipofuscinoses (9), and the Syndromic

Epilepsy and Intellectual Disability (ID; 93) Subpanels. The Microcephaly Panel includes conditions such as microcephaly,

holoprosencephaly, lisencephaly, and other brain malformations for differential diagnosis. These genes were selected for

inclusion based on literature review, clinical actionability scores, and comparison with commercially available assays. Further

information about these genes and panels is available in the following pages.

Customizable testing is available for ordering a neurodevelopment disease group-specific gene panel. Targeted familial

testing for a specific variant is also available. Parental testing is recommended. Sema4 offers whole exome sequencing if

needed. Genetic testing may clarify the cause of an individual’s neurodevelopmental disease, provide information on the

likelihood of related health issues, and also establish risk to other family members and future generations.

The American College of Medical Genetics (ACMG) recommends that every person with developmental delay, ID, or ASD

should receive a chromosomal microarray (CMA) to identify copy number variants (CNVs) that contribute to risk in 10-15%

of individuals. Sema4 offers CMA testing as a first-tier test and an ultra-high resolution medical exome array for exon-level

CNV detection as an add-on to NGS.

Genetics

The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), -linked (XL),

or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated gene

has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant,

meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally,

these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display

differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to

have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate

carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked inheritance means

that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the

X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked diseases are normally

transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but

will not occur from father to son. An IC mode of inheritance indicates no prior family history.

Indications

1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unknown status (no

screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose

of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known

variant(s).

2. Treatment: to clarify the cause of an individual’s neurodevelopmental disease, provide information on the likelihood of

related health issues, and guide treatment.

(6)

For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated

subpanels prior to ordering the comprehensive panel.

Testing Methods, Sensitivity, and Limitations

Next Generation Sequencing (NGS) (Analytical Detection Rate >95%)

Agilent SureSelect

TM

_{QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice}

junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that contain previously reported

mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp

paired-end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In

our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X.

The coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the average depth of

coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across

the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping

or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In

addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19

coordinates) have been excluded due to lack of amenability to NGS or Sanger sequencing, high GC content, high homology,

lack of known clinically significant variants, or overlap with repetitive regions: ALDH7A1 chr5:125907050-125907056, ARX

chrX:25031027-25031926, ATP13A2 chr1:17338212-17338244, ATP2A2 chr12:110718408-110718414, ATP6AP2

chrX:40440306-40440365, ATP7A chrX:77269723-77269729, ATP7A chrX:77278955-77279156, ATR

chr3:142184699-142184705, CACNA1H chr16:1203726-1204047, CACNA2D2 chr3:50540637-50540865, CDKN1C

chr11:2905888-2906730, CHRNA7 chr15:32460129-32460670, CHRNA7 chr15:32446096-32446198, COL18A1

chr21:46825134-46825167, COL18A1 chr21:46825282-46825399, DMD chrX:31897426-31897627, DMD chrX:32668999-32669253, DMD

chrX:32644476-32644680, DMD chrX:31627637-31627838, DMD chrX:32460213-32460334, DMD

chrX:31219361-31219367, DMD chrX:31219126-31219287, DMD chrX:32644160-32644321, EHMT1 chr9:140513469-140513512, ELP4

chr11:31703323-31703634, EPM2A chr6:146056322-146056645, FKTN chr9:108368751-108368962, FMR1

chrX:147018844-147019305, GABRD chr1:1950851-1950941, GK chrX:30687487-30687493, HGSNAT

chr8:42995524-42995881, HPRT1 chrX:133625461-133625467, HTRA1 chr10:124221157-124221651, IDS chrX:148584720-148585050,

IQSEC2 chrX:53263389-53264377, KRIT1 chr7:91829915-91829921, LAMP2 chrX:119604075-119604081, MAGI2

chr7:77648620-77649304, NFIX chr19:13106640-13106689, NHS chrX:17753589-17753595, NOTCH3

chr19:15311587-15311727, OTC chrX:38269298-38269509, SCN1B chr19:35521713-35521775, SCN3A chr2:165986438-165986817,

SGSH chr17:78193967-78194168, ST3GAL5 chr2:86115935-86116039, SYNGAP1 chr6:33388030-33388119, TBX1

chr22:19748416-19748814, TMLHE chrX:154721184-154721338, TMLHE chrX:154722214-154722372, TMLHE

chrX:154722006-154722167, TRIO chr5:14143823-14144002, TUBB2A chr6:3154085-3155190, TUBB2A

chr6:3156266-3156397, TUBB2B chr6:3224973-3226056, VPS13A chr9:79829178-79829419, and ZIC2 chr13:100637565-100637947.

The exons contained within these regions will not be reflexed to Sanger sequencing if the mapping quality or coverage is

poor due to high sequence homology. Any clinically significant variants identified during testing in these regions are confirmed

by a second method and reported. Analysis of SHANK2 and SHANK3 is limited to copy number variants only.

This test will detect variants within the exons and the intron-exon boundaries of the target regions. Variants outside these

regions may not be detected, including, but not limited to, UTRs, promoters, and deep intronic areas, or regions that fall into

the exceptions mentioned above. This technology may not detect all small insertion/deletions and is not diagnostic for repeat

expansions and structural genomic variation. In addition, a mutation(s) in a gene not included on the panel could be present

in this patient.

Copy Number Variant Analysis (Analytical Detection Rate >90%)

Large duplications and deletions were called from the relative read depths on an exon-by-exon basis using a custom Exome

Hidden Markov Model (XHMM) algorithm. This algorithm is designed to pick up deletions and duplications of two or more

exons/probed regions in length. For deletions (≥2 exons/probed regions), the analytical sensitivity and analytical specificity

are >99%. For duplications (≥2 exons/probed regions), the analytical sensitivity is >80% and analytical specificity is >99%. All

reported pathogenic or likely pathogenic deletions and/or duplications were confirmed by a custom aCGH platform,

quantitative PCR, and/or MLPA, depending on CNV size and gene content.

(7)

Fragile X CGG Repeat Analysis (Analytical Detection Rate >99%)

Polymerase Chain Reaction (PCR) amplification using Asuragen, Inc. AmplideX® FMR1 PCR reagents followed by capillary

electrophoresis for allele sizing is performed. Samples positive for FMR1 CGG repeats in the premutation and full mutation

size range are further analyzed by Southern blot analysis to assess the size and methylation status of the FMR1 CGG repeat.

Targeted Genotyping using Agena® MassARRAY® (Analytical Detection Rate >99%)

Targeted genotyping is performed to ensure sample identity quality control and to test complex variants, using multiplex

Polymerase Chain Reaction (PCR) and multiplex Single Base Extension (SBE) reaction with Agena® SpectroCHIP® II on a

MassARRAY® Analyzer 4 system.

Multiplex Ligation-Dependent Probe Amplification (MLPA) (Analytical Detection Rate >99%)

MLPA® probe sets and reagents from MRC-Holland are used for copy number analysis of specific targets versus known

control samples. False positive or negative results may occur due to rare sequence variants in target regions detected by

MLPA probes. Analytical sensitivity and specificity of the MLPA method are both 99%. MLPA for Duchenne muscular

dystrophy disease (DMD) will only be performed if indicated. For Duchenne muscular dystrophy, the copy numbers of all

DMD exons are analyzed. Potentially pathogenic single exon deletions and duplications are confirmed by a second method.

Analysis of DMD is performed in association with sequencing of the coding regions.

Exon Array (Confirmation method) (Accuracy >99%)

The customized oligonucleotide microarray (Oxford Gene Technology) is a highly-targeted exon-focused array capable of

detecting medically relevant microdeletions and microduplications at a much higher resolution than traditional aCGH methods.

Each array matrix has approximately one hundred and eighty thousand 60-mer oligonucleotide probes that cover the entire

gene panel. This platform is designed based on human genome NCBI Build 37 (hg19) and the CGH probes are selected to

target the exonic regions of 410 genes. This test does not include analysis of ADNP, ATRIP, COMT, CTCF, CYP2B6,

CYP2D6, DEPDC5, EEF1A2, GABRB2, GATAD2B, GNAO1, GNB1, GRIK4, HTR2A, KCNA2, KCNB1, KIF2A, MTOR,

NECAP1, NPRL2, NPRL3, OPRM1, PURA, SETD5, SIK1, SLC12A5, SLC13A5, SLC1A2, SLC25A1, SLC35A2, SOX11,

STX1B, SZT2, TBR1, TCF12, TCF20, TUBB, TUBB2A, TUBG1, UGT2B15, WAC, ZMYND11, and ZNF407. For the majority

of genes there are a minimum of 4 probes per exon. For very large exons, probes are distributed evenly along the exon with

1 probe every 125 bp. In the untargeted backbone regions, this array has one probe every 42kb. All genomic coordinates

are reported using human genome NCBI Build 37 (hg19). Copy number aberrations are identified using the Aberration

Detection Method-2 (ADM2) algorithm with a sensitivity threshold of 6.0 (Agilent Technologies). The log

2

ratio threshold

values to detect aberrations are < -0.25 for copy number losses and > 0.25 for copy number gains. Please note that any

inconsistencies in the reported biological familial relationships could significantly change the interpretation of these results.

For reported CNVs with uncertain clinical significance, continued surveillance of the medical literature for new information is

recommended.

The sensitivity of this assay is estimated to be greater than 99% for microdeletions and microduplications in the exonic regions

of 410 medically-relevant genes. Variant interpretation and classification is performed based on the American College of

Medical Genetics standards and guidelines for the interpretation of sequence variants (Richards et al, 2015). Frequency in

control populations is evaluated based on the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), the

Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home), and 1000 genomes (http://www.1000genomes.org/)

databases. Any benign polymorphisms identified during this analysis will not be reported. Variant interpretations, based on

current knowledge, may change over time as more information arises.

The following aberrations will

NOT be reported and parental studies will NOT be performed:

• _{CNVs that are considered benign based on coverage in the Database of Genomic Variants (DGV; <http://dgv.tcag.ca/>)}

and/or our internal laboratory CNV database

• Gains or losses of <500 kb that do not include any known genes (<http://www.ncbi.nlm.nih.gov/refseq/>)

• Gains or losses with no known clinical significance (based on gene content and/or coverage in the DGV)

(8)

GNAO1, GNB1, GRIK4, HTR2A, KCNA2, KCNB1, KIF2A, MTOR, NECAP1, NPRL2, NPRL3, OPRM1, PURA, SETD5,

SIK1, SLC12A5, SLC13A5, SLC1A2, SLC25A1, SLC35A2, SOX11, STX1B, SZT2, TBR1, TCF12, TCF20, TUBB,

TUBB2A, TUBG1, UGT2B15, WAC, ZMYND11, or ZNF407.

• _{Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic alleles, and}

cancer predisposition

• _{Copy number gains and losses that are < 1.0 Mb in size and that appear to be mosaic by aCGH due to atypical log}

2

ratios, unless the affected region is determined to be clinically significant based on gene content and/or coverage in the

DGV

The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian

translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology

will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting

defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any

locus does not exclude the diagnosis of any of the disorders represented on the microarray.

Quantitative PCR (Confirmation method) (Accuracy >99%)

The relative quantification PCR is utilized on a Roche Universal Library Probe (UPL) system, which relates the PCR signal of

the target region in one group to another. To test for genomic imbalances, both sample DNA and reference DNA is amplified

with primer/probe sets that specific to the target region and a control region with known genomic copy number. Relative

genomic copy numbers are calculated based on the standard ∆∆Ct formula.

Sanger Sequencing (Confirmation method) (Accuracy >99%)

Sanger sequencing, as indicated, is performed using BigDye Terminator chemistry with the ABI 3730 DNA analyzer with

target specific amplicons. It also may be used to supplement specific guaranteed target regions that fail NGS sequencing due

to poor quality or low depth of coverage (<20 reads) or as a confirmatory method for NGS positive results. False negative

results may occur if rare variants interfere with amplification or annealing.

Variant Interpretation and Reporting

Variant interpretation and classification was performed based on the American College of Medical Genetics Standards

and guidelines for the interpretation of sequence variants (PMID:25741868). Frequency in control populations were

evaluated based on the Exome Aggregation Consortium (ExAC,

http://exac.broadinstitute.org/

) , and Genome Aggregation

Database (gnomAD,

http://gnomad.broadinstitute.org/

). Potentially pathogenic variants may be confirmed by Sanger

sequencing if indicated. Familial samples are only tested for certain variants by Sanger sequencing if indicated. Variants

classified as likely benign in the proband were not confirmed by Sanger sequencing. We cannot rule out the possibility that

variants classified as uncertain clinical significance may contribute to disease. Any benign polymorphisms identified during

this analysis were not reported. Variant interpretations, based on current knowledge, may change over time as more

information arises.

Turnaround Time

Results are reported to the referring physician within 10-14 business days (for prenatal samples) and 3-4 weeks (for postnatal

samples) from the receipt of the specimen. Please note only targeted analysis is performed for prenatal cases, where the

familial gene and mutation(s) are known.

Specimen and Shipping Requirements

Postnatal blood samples: 2 yellow-top (ACD-A or ACD-B) or 2 lavender-top (EDTA) tubes, 5-10 mL of blood from the

patient are required. One blood tube from both parents is requested.

Newborn/child: 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) tube, 2 mL of blood from the patient are required.

(9)

Prenatal Specimens: 2 confluent T-25 flasks of cultured cells (originating from amniotic fluid or chorionic villi) or more than

4 mg of direct CVS tissue, or 15 mL of direct amniotic fluid (AF) as well as 1 lavender-top (EDTA) 5-10mL tube of blood from

the pregnant patient and her partner are required. Note: parental blood samples are requested for confirmation studies

necessary in some cases; maternal blood is also used for maternal cell contamination studies. Please note, prenatal analysis

will only be performed for known parental variants.

Extracted DNA samples: We request 20 µL DNA (50-250 ng/µL) or at minimum require 10 µL DNA (50-250 ng/µL). Causes

for rejection include impurities in the test or reference DNA samples, including NaCl or KCl (>40 mM) and other salts, phenol,

ethanol, heparin, EDTA (>1.5 mM), and Fe, contaminated DNA, and low concentration of DNA (<20 ng/µL).

Saliva samples: We can accept saliva specimens upon request. Saliva samples should be collected in Oragene DNA

(OG-500) kits by DNA Genotek. Please contact our laboratory to obtain saliva kits.

Cheek swab: 1 cheek swab specimen collected from ORAGENE kit from the patient is required. 1 cheek swab specimen

collected from ORAGENE kit from both parents is requested.

Tubes of blood, cultured cells, direct CVS, and direct AF should be kept and shipped refrigerated or at room

temperature (PLEASE DO NOT FREEZE). Please note that additional samples may be required for exon array

studies if ordered.

Customer Services and Genetic Counseling

Include the following with each sample:

• Completed and signed test requisition form and informed consent

• Billing information or payment (include copy of insurance card)

• Contact information for referring physician

• Testing to be performed

• Indication for testing, patient’s family history, ethnic background and prior relevant test results

Send same day or overnight (check for morning delivery) to:

Sema4

62 Southfield Avenue

Stamford, CT 06902

Contact:

[email protected]

Tel: 800.298.6470

Fax: 646.859.6870

(10)

THE COMPREHENSIVE

EPILEPSY AND AUTISM PANEL

The Comprehensive Epilepsy and Autism Panel includes 401 genes associated with syndromic and non-syndromic causes

of autism spectrum disorder (ASD), intellectual disability, and epilepsy. Given the clinical overlap between these disorders,

comprehensive testing allows time- and cost-effective evaluations of multiple conditions. The Comprehensive Epilepsy and

Autism Panel (401 genes) includes the Comprehensive Autism Spectrum Disorder Panel (228) and the Comprehensive

Epilepsy (226) panels. Epilepsy subpanels include Focal, Generalized, and Myoclonic Epilepsy (52), Infantile Epilepsies (58),

Migraine (7), Neuronal Migration (22), Neuronal Ceroid Lipofuscinoses (9), and Syndromic Epilepsy and Intellectual Disability

(93) Subpanels. Please see the following sections for detailed descriptions of each of the subgroups.

The Comprehensive Epilepsy and Autism Panel includes the following 401 genes.

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance

ABAT 137150 613163: AR GABA-transaminase deficiency Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

ABCD1 300371 300100: XLR Adrenoleukodystrophy _{300100: XLR Adrenomyeloneuropathy, adult} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

ACSL4 300157 300387: XLD Mental retardation, XL 63 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD, XL

ACY1 104620 609924: AR Aminoacylase 1 deficiency Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

And Myoclonic Epilepsy AR

ADGRG1 604110 606854: AR Polymicrogyria, bilateral frontoparietal

615752: Polymicrogyria, bilateral perisylvian

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Migration;

Microcephaly AR

ADGRV1 602851

604352: AD ?Febrile seizures, familial, 4 605472: AR Usher syndrome, type 2C 605472: AR Usher syndrome, type 2C, GPR98/PDZD7 digenic

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

And Myoclonic Epilepsy AD, AR

ADNP 611386 615873: AD Helsmoortel-van der Aa syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

ADSL 608222 103050: AR Adenylosuccinase deficiency Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy;

Comprehensive Autism Spectrum Disorder AR

AFF2 300806 309548: XLR Mental retardation, XL, FRAXE _type Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

AGO1 606228 None Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} None

AHI1 608894 608629: AR Joubert syndrome 3 Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

STAT Autism Spectrum Disorder AR

AIFM1 300169

300816: XLR Combined oxidative phosphorylation deficiency 6 310490: XLR Cowchock syndrome 300614: XLR Deafness, XL 5

Comprehensive Epilepsy And Autism;

Comprehensive Autism Spectrum Disorder XLR, XL

ALDH5A1 610045 271980: AR Succinic semialdehyde _{dehydrogenase deficiency}

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized, And Myoclonic Epilepsy; Comprehensive Autism Spectrum Disorder

AR

ALDH7A1 107323 266100: AR Epilepsy, pyridoxine-dependent Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

ALG13 300776

300884: XLD ?Congenital disorder of glycosylation, type Is

300884: XLD Epileptic encephalopathy, early infantile, 36

Comprehensive Epilepsy; Infantile Epilepsy XLD

AMT 238310 605899: AR Glycine encephalopathy Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

ANK3 600465 615493: AR ?Mental retardation, AR, 37 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

ANKRD11 611192 148050: AD KBG syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

AP1S2 300629 304340: XLR Mental retardation, XL syndromic ₅ Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

(11)

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance Autism Spectrum Disorder; STAT Autism

Spectrum Disorder

AP4B1 607245 614066: AR Spastic paraplegia 47, AR Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

AP4E1 607244 613744: AR Spastic paraplegia 51, AR _{184450: AD Stuttering, familial persistent, 1} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD, AR

AP4M1 602296 612936: AR Spastic paraplegia 50, AR Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

AP4S1 607243 614067: AR Spastic paraplegia 52, AR Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

ARFGEF2 605371 608097: AR Periventricular heterotopia with _microcephaly Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability; Microcephaly AR

ARHGEF9 300429 300607: XLR Epileptic encephalopathy, early _{infantile, 8} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} XLR

ARID1A 603024 614607: AD Coffin-Siris syndrome 2 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

ARID1B 614556 135900: AD Coffin-Siris syndrome 1 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

ARX 300382

308350: XLR Epileptic encephalopathy, early infantile, 1

300215: XL Hydranencephaly with abnormal genitalia

300215: XL Lissencephaly, XL 2

300419: XLR Mental retardation, XL 29 and others

309510: XLR Partington syndrome 300004: XL Proud syndrome

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy; Comprehensive Autism Spectrum Disorder; STAT Autism Spectrum Disorder; Microcephaly

XLR, XL

ASPM 605481 608716: AR Microcephaly 5, primary, AR Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

ATP13A2 610513 606693: AR Kufor-Rakeb syndrome _{617225: AR Spastic paraplegia 78, AR} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

ATP1A2 182340

104290: AD Alternating hemiplegia of childhood 1

602481: AD Migraine, familial basilar 602481: AD Migraine, familial hemiplegic, 2

Comprehensive Epilepsy; Migraine AD

ATP2A2 108740 101900: AD Acrokeratosis verruciformis _{124200: AD Darier disease} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability AD

ATP6AP2 300556 300423: XLR Mental retardation, XL, syndromic, Hedera type

300911: XLR ?Parkinsonism with spasticity, XL

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability XLR, XL

ATP6V0A2 611716 219200: AR Cutis laxa, AR, type IIA _{278250: AR Wrinkly skin syndrome} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability AR

ATP7A 300011

309400: XLR Menkes disease 304150: XLR Occipital horn syndrome 300489: XLR Spinal muscular atrophy, distal, XL 3

ATP8A2 605870 615268: AR ?Cerebellar ataxia, mental _{retardation, and dysequilibrium syndrome 4} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

ATR 601215 614564: AD ?Cutaneous telangiectasia and cancer syndrome, familial 210600: AR Seckel syndrome 1

And Intellectual Disability; Microcephaly AD, AR

ATRX 300032 300448: Alpha-thalassemia myelodysplasia syndrome, somatic 301040: XLD Alpha-thalassemia/mental retardation syndrome 309580: XLR Mental retardation-hypotonic facies syndrome, XL

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy And Intellectual Disability; Comprehensive Autism Spectrum Disorder

XLD, XLR, XL

AUTS2 607270 615834: AD Mental retardation, AD 26 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

BCKDK 614901 614923: Branched-chain ketoacid _{dehydrogenase kinase deficiency}

(12)

BCL11A 606557 617101: AD Dias-Logan syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

BCOR 300485 300166: XLD Microphthalmia, syndromic 2 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD

BRAF 164757

211980: Adenocarcinoma of lung, somatic 115150: AD Cardiofaciocutaneous syndrome Colorectal cancer, somatic (3)

613707: AD LEOPARD syndrome 3 Melanoma, malignant, somatic (3) Nonsmall cell lung cancer, somatic (3) 613706: AD Noonan syndrome 7

Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

Noonan Syndrome AD

BRWD3 300553 300659: XLR Mental retardation, XL 93 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

C12ORF57 615140 218340: AR Temtamy syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

CA8 114815 613227: AR Cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3

CACNA1A 601011

617106: AD Epileptic encephalopathy, early infantile, 42

108500: AD Episodic ataxia, type 2 141500: AD Migraine, familial hemiplegic, 1 141500: AD Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia

183086: AD Spinocerebellar ataxia 6

Comprehensive Epilepsy; Migraine AD

CACNA1C 114205 611875: Brugada syndrome 3 _{601005: AD Timothy syndrome} Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

STAT Autism Spectrum Disorder AD

CACNA1H 607904

611942: {Epilepsy, childhood absence, susceptibility to, 6}

611942: {Epilepsy, idiopathic generalized, susceptibility to, 6}

617027: AD Hyperaldosteronism, familial, type IV

And Myoclonic Epilepsy AD

CACNA2D2 607082 None Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

And Myoclonic Epilepsy None

CACNB4 601949

607682: AD {Epilepsy, idiopathic generalized, susceptibility to, 9}

607682: AD {Epilepsy, juvenile myoclonic, susceptibility to, 6}

613855: AD Episodic ataxia, type 5

CASK 300172

300422: FG syndrome 4

300749: XLD Mental retardation and microcephaly with pontine and cerebellar hypoplasia

300422: Mental retardation, with or without nystagmus

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy And Intellectual Disability; Comprehensive Autism Spectrum Disorder; Microcephaly

XLD

CASR 601199

{Calcium, serum level of} (3)

612899: {Epilepsy idiopathic generalized, susceptibility to, 8}

Hypercalciuric hypercalcemia (3) 239200: AR, AD Hyperparathyroidism, neonatal

601198: AD Hypocalcemia, AD

601198: AD Hypocalcemia, AD, with Bartter syndrome

145980: AD Hypocalciuric hypercalcemia, type I

CBL 165360

607785: AD, SM ?Juvenile myelomonocytic leukemia

613563: AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia

Noonan Syndrome AD, SM

CC2D1A 610055 608443: AR Mental retardation, AR 3 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

(13)

CCDC88C 611204 236600: AR Hydrocephalus, congenital, 1 _{616053: AD ?Spinocerebellar ataxia 40} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability AD, AR

CCM2 607929 603284: AD Cerebral cavernous _{malformations-2} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CDKL5 300203 300672: XLD Epileptic encephalopathy, early _{infantile, 2}

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy; Comprehensive Autism Spectrum Disorder; STAT Autism Spectrum Disorder; Microcephaly

XLD

CDKN1C 600856 130650: AD Beckwith-Wiedemann syndrome _{614732: AD IMAGE syndrome} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

CHD2 602119 615369: AD Epileptic encephalopathy, _{childhood-onset} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy;

Comprehensive Autism Spectrum Disorder AD

CHD7 608892 214800: AD CHARGE syndrome 612370: AD Hypogonadotropic hypogonadism

5 with or without anosmia

CHD8 610528 615032: AD {Autism, susceptibility to, 18} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

CHRNA2 118502 610353: AD Epilepsy, nocturnal frontal lobe, _{type 4} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CHRNA4 118504 600513: AD Epilepsy, nocturnal frontal lobe, 1 _{188890: {Nicotine addiction, susceptibility to}} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CHRNA7 118511 None Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CHRNB2 118507 605375: Epilepsy, nocturnal frontal lobe, 3 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CLCN2 600570

607628: AD {Epilepsy, idiopathic generalized, susceptibility to, 11}

607628: AD {Epilepsy, juvenile absence, susceptibility to, 2}

607628: AD {Epilepsy, juvenile myoclonic, susceptibility to, 8}

615651: AR Leukoencephalopathy with ataxia

CLCN4 302910 300114: XLR Mental retardation, XL 49/15 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

CLN3 607042 204200: AR Ceroid lipofuscinosis, neuronal, 3 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AR

CLN5 608102 256731: AR Ceroid lipofuscinosis, neuronal, 5 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AR

CLN6 606725 601780: AR Ceroid lipofuscinosis, neuronal, 6 204300: AR Ceroid lipofuscinosis, neuronal,

Kufs type, adult onset

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AR

CLN8 607837 600143: AR Ceroid lipofuscinosis, neuronal, 8 610003: AR Ceroid lipofuscinosis, neuronal, 8,

Northern epilepsy variant

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AR

CNTNAP2 604569

612100: {Autism susceptibility 15}

610042: AR Cortical dysplasia-focal epilepsy syndrome

610042: AR Pitt-Hopkins like syndrome 1

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized, And Myoclonic Epilepsy; Syndromic Epilepsy And Intellectual Disability; Comprehensive Autism Spectrum Disorder; STAT Autism Spectrum Disorder

AR

COL18A1 120328 267750: AR Knobloch syndrome, type 1 Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Neuronal Migration} AR

COL4A1 120130

611773: AD Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps 607595: AD Brain small vessel disease with or without ocular anomalies

614519: {Hemorrhage, intracerebral, susceptibility to}

(14)

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance 175780: AD Porencephaly 1

180000: AD ?Retinal arteries, tortuosity of 269160: Schizencephaly

CPA6 609562 614417: AR, AD Epilepsy, familial temporal lobe, 5

614418: AR Febrile seizures, familial, 11

CREBBP 600140 180849: AD Rubinstein-Taybi syndrome 1

AD

CSTB 601145 254800: AR Epilepsy, progressive myoclonic _{1A (Unverricht and Lundborg)} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

CTCF 604167 615502: AD Mental retardation, AD 21 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

CTNNB1 116806

114500: Colorectal cancer, somatic 617572: AD Exudative vitreoretinopathy 7 114550: Hepatocellular carcinoma, somatic 155255: Medulloblastoma, somatic 615075: AD Mental retardation, AD 19 167000: Ovarian cancer, somatic 132600: Pilomatricoma, somatic

CTSD 116840 610127: AR Ceroid lipofuscinosis, neuronal, 10 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AR

CUL3 603136 614496: AD Pseudohypoaldosteronism, type _IIE Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

CUL4B 300304 300354: XLR Mental retardation, XL, _{syndromic 15 (Cabezas type)} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability XLR, XL

CYP27A1 606530 213700: AR Cerebrotendinous xanthomatosis Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

D2HGDH 609186 600721: AR D-2-hydroxyglutaric aciduria Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

DCX 300121 300067: XL Lissencephaly, XL _{300067: XL Subcortical laminal heterotopia, XL} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability; Microcephaly XL

DDHD2 615003 615033: AR Spastic paraplegia 54, AR Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

DDX3X 300160 300958: XLR, XLD Mental retardation, XL 102 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD, XLR, _XL

DEAF1 602635 617171: AR ?Dyskinesia, seizures, and intellectual developmental disorder

615828: AD Mental retardation, AD 24

Comprehensive Autism Spectrum Disorder AD, AR

DEPDC5 614191 604364: AD Epilepsy, familial focal, with _{variable foci 1} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

DHCR7 602858 270400: AR Smith-Lemli-Opitz syndrome Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

STAT Autism Spectrum Disorder; Microcephaly AR

DIS3L2 614184 267000: AR Perlman syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

DKC1 300126 305000: XLR Dyskeratosis congenita, XL Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

DLG3 300189 300850: XLR Mental retardation, XL 90 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

DMD 300377 300376: XLR Becker muscular dystrophy 302045: XL Cardiomyopathy, dilated, 3B 310200: XLR Duchenne muscular dystrophy

DNAJC5 611203 162350: AD Ceroid lipofuscinosis, neuronal, 4, _{Parry type} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Neuronal Ceroid

Lipofuscinoses AD

DNM1 602377 616346: AD Epileptic encephalopathy, early _{infantile, 31} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AD

(15)

DOCK7 615730 615859: AR Epileptic encephalopathy, early _{infantile, 23} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

DPYD 612779 274270: AR Dihydropyrimidine dehydrogenase deficiency

274270: AR 5-fluorouracil toxicity

DYNC1H1 600112

614228: AD Charcot-Marie-Tooth disease, axonal, type 20

614563: AD Mental retardation, AD 13 158600: AD Spinal muscular atrophy, lower extremity-predominant 1, AD

Microcephaly AD

DYRK1A 600855 614104: AD Mental retardation, AD 7

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy; Syndromic Epilepsy And Intellectual Disability; Comprehensive Autism Spectrum Disorder

AD

EBP 300205 302960: XLD Chondrodysplasia punctata, XLD _{300960: XLR MEND syndrome} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD, XLR

EEF1A2 602959 616409: AD Epileptic encephalopathy, early infantile, 33

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy;

Syndromic Epilepsy And Intellectual Disability AD

EFHC1 608815

607631: AD {Epilepsy, juvenile absence, susceptibility to, 1}

254770: AD {Myoclonic epilepsy, juvenile, susceptibility to, 1}

EHMT1 607001 610253: AD Kleefstra syndrome 1

AD

EIF2S3 300161 300148: XLR MEHMO syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

ELP4 606985 617141: AD ?Aniridia 2 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

EMX2 600035 269160: Schizencephaly Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Neuronal Migration} None

EPM2A 607566 254780: AR Epilepsy, progressive myoclonic _{2A (Lafora)} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

EZH2 601573 277590: AD Weaver syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

FGD1 300546 305400: XLR Aarskog-Scott syndrome 305400: XLR Mental retardation, XL syndromic

16

XLR, XL

FGFR3 134934

100800: AD Achondroplasia 109800: Bladder cancer, somatic 610474: AR, AD CATSHL syndrome 603956: Cervical cancer, somatic 114500: Colorectal cancer, somatic 612247: AD Crouzon syndrome with acanthosis nigricans

146000: AD Hypochondroplasia 149730: AD LADD syndrome 602849: AD Muenke syndrome 162900: Nevus, epidermal, somatic 616482: AD SADDAN

273300: Spermatocytic seminoma, somatic 187600: AD Thanatophoric dysplasia, type I 187601: AD Thanatophoric dysplasia, type II

Comprehensive Epilepsy; Neuronal Migration AD, AR

FKRP 606596

613153: AR Muscular

dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5

606612: AR Muscular

dystrophy-dystroglycanopathy (congenital with or without mental retardation), type B, 5

607155: AR Muscular

dystrophy-dystroglycanopathy (limb-girdle), type C, 5

Microcephaly AR

(16)

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance 300321: XL ?FG syndrome 2 305620: XLR Frontometaphyseal dysplasia 1 300049: XLD Heterotopia, periventricular 300048: XLR Intestinal pseudoobstruction, neuronal 309350: XLD Melnick-Needles syndrome 311300: XLD Otopalatodigital syndrome, type I 304120: XLD Otopalatodigital syndrome, type II

300244: XLD Terminal osseous dysplasia

FLVCR2 610865 225790: AR Proliferative vasculopathy and _{hydranencephaly-hydrocephaly syndrome} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

FMR1 309550 300624: XLD Fragile X syndrome 300623: XLD Fragile X tremor/ataxia syndrome

311360: XL Premature ovarian failure 1

STAT Autism Spectrum Disorder XLD, XL

FOLR1 136430 613068: AR Neurodegeneration due to _{cerebral folate transport deficiency}

AR

FOXG1 164874 613454: AD Rett syndrome, congenital variant

AD

FOXP1 605515 613670: AD Mental retardation with language _{impairment and with or without autistic features} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

FOXP2 605317 602081: AD Speech-language disorder-1 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

FTSJ1 300499 309549: XLR Mental retardation, XL 9/44 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR, XL

GABRA1 137160

611136: {Epilepsy, juvenile myoclonic, susceptibility to, 5}

Comprehensive Epilepsy; Infantile Epilepsy AD

GABRB2 600232 617829: AD Epileptic encephalopathy, infantile _{or early childhood, 2} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AD

GABRB3 137192

GABRD 137163

613060: AD {Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to} 613060: AD {Epilepsy, idiopathic generalized, 10}

613060: AD {Epilepsy, juvenile myoclonic, susceptibility to}

GABRG2 137164

607681: AD {Epilepsy, childhood absence, susceptibility to, 2}

611277: AD Epilepsy, generalized, with febrile seizures plus, type 3

611277: AD Febrile seizures, familial, 8

GAMT 601240 612736: AR Cerebral creatine deficiency _{syndrome 2} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

GATAD2B 614998 615074: AD Mental retardation, AD 18 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

GATM 602360 612718: AR Cerebral creatine deficiency _{syndrome 3} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

GCSH 238330 605899: AR ?Glycine encephalopathy Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

GDI1 300104 300849: XLD Mental retardation, XL 41 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD, XL

(17)

GLDC 238300 605899: AR Glycine encephalopathy Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

GLI2 165230 615849: AD Culler-Jones syndrome _{610829: AD Holoprosencephaly 9} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability; Microcephaly AD

GLI3 165240

175700: AD Greig cephalopolysyndactyly syndrome

241800: {Hypothalamic hamartomas, somatic} 146510: AD Pallister-Hall syndrome

174200: AD Polydactyly, postaxial, types A1 and B

174700: AD Polydactyly, preaxial, type IV

GNAO1 139311

617493: AD Neurodevelopmental disorder with involuntary movements

GNB1 139380 613065: Leukemia, acute lymphoblastic, somatic

And Myoclonic Epilepsy; Infantile Epilepsy AD

GNS 607664 252940: AR Mucopolysaccharidosis type IIID Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

GOSR2 604027 614018: AR Epilepsy, progressive myoclonic 6 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

GPC3 300037 312870: XLR Simpson-Golabi-Behmel syndrome, type 1

194070: Wilms tumor, somatic

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy And Intellectual Disability; Comprehensive Autism Spectrum Disorder; STAT Autism Spectrum Disorder

XLR

GPHN 603930 615501: AR Molybdenum cofactor deficiency C Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

GRIA3 305915 300699: XLR Mental retardation, XL 94

XLR, XL

GRIK2 138244 611092: AR Mental retardation, AR, 6 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

GRIN1 138249

614254: AD Neurodevelopmental disorder with or without hyperkinetic movements and seizures, AD

617820: AR Neurodevelopmental disorder with or without hyperkinetic movements and seizures, AR

GRIN2A 138253 245570: AD Epilepsy, focal, with speech _{disorder and with or without mental retardation} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

GRIN2B 138252 616139: AD Epileptic encephalopathy, early infantile, 27

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy;

GRIP1 604597 617667: AR Fraser syndrome 3 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

HCCS 300056 309801: XLD Linear skin defects with multiple _{congenital anomalies 1} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD

HCN1 602780 615871: AD Epileptic encephalopathy, early _{infantile, 24} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AD

HCN4 605206 613123: Brugada syndrome 8 _{163800: AD Sick sinus syndrome 2} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

HDAC8 300269 300882: XLD Cornelia de Lange syndrome 5 Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

Microcephaly XLD

HGSNAT 610453 252930: AR Mucopolysaccharidosis type IIIC (Sanfilippo C)

616544: AR Retinitis pigmentosa 73

(18)

HNRNPU 602869 617391: AD Epileptic encephalopathy, early _{infantile, 54} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

HPRT1 308000 300323: XLR HPRT-related gout _{300322: XLR Lesch-Nyhan syndrome} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

HRAS 190020

109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles

218040: AD, IC Costello syndrome 162900: {Nevus sebaceous or woolly hair nevus, somatic}

163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic}

Noonan Syndrome AD, IC

HSD17B10 300256 300438: XLD HSD10 mitochondrial disease Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability XLD

HTRA1 602194

600142: AR CARASIL syndrome

616779: AD Cerebral arteriopathy, AD, with subcortical infarcts and leukoencephalopathy, type 2

610149: {Macular degeneration, age-related, 7} 610149: {Macular degeneration, age-related, neovascular type}

HUWE1 300697 300706: Mental retardation, XL syndromic, _{Turner type} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XL

IDS 300823 309900: XLR Mucopolysaccharidosis II Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

IL1RAPL1 300206 300143: XLR Mental retardation, XL 21/34 Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

STAT Autism Spectrum Disorder XLR, XL

IQSEC2 300522 309530: XLD Mental retardation, XL 1/78 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

And Intellectual Disability XLD, XL

ITPA 147520 616647: AR Epileptic encephalopathy, early infantile, 35

613850: [Inosine triphosphatase deficiency]

Comprehensive Epilepsy; Infantile Epilepsy AR

KANSL1 612452 610443: AD Koolen-De Vries syndrome Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

KAT6A 601408 616268: AD Mental retardation, AD 32 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

KAT6B 605880 606170: AD Genitopatellar syndrome _{603736: AD SBBYSS syndrome} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

KCNA1 176260 160120: AD Episodic ataxia/myokymia _syndrome Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

KCNA2 176262 616366: AD Epileptic encephalopathy, early _{infantile, 32} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy;

Syndromic Epilepsy And Intellectual Disability AD

KCNB1 600397 616056: AD Epileptic encephalopathy, early _{infantile, 26} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AD

KCNJ1 600359 241200: AR Bartter syndrome, type 2 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

KCNJ10 602208 600791: AR Enlarged vestibular aqueduct, digenic

612780: AR SESAME syndrome

KCNJ11 600937

610582: AD Diabetes mellitus, transient neonatal, 3

125853: AD {Diabetes mellitus, type 2, susceptibility to}

606176: AR, AD Diabetes, permanent neonatal, with or without neurologic features 601820: AR Hyperinsulinemic hypoglycemia,

(19)

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance familial, 2

616329: AD Maturity-onset diabetes of the young, type 13

KCNMA1 600150

617643: AR ?Cerebellar atrophy, developmental delay, and seizures 609446: AD Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy

KCNQ2 602235

121200: AD Myokymia

121200: AD Seizures, benign neonatal, 1

KCNQ3 602232 121201: AD Seizures, benign neonatal, 2 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

KCNT1 608167 615005: AD Epilepsy, nocturnal frontal lobe, 5 614959: AD Epileptic encephalopathy, early

infantile, 14

KCTD13 608947 None Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} None

KCTD7 611725 611726: AR Epilepsy, progressive myoclonic 3, _{with or without intracellular inclusions} Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Focal, Generalized,

KDM5C 314690 300534: XLR Mental retardation, XL, _{syndromic, Claes-Jensen type}

XLR, XL

KDM6A 300128 300867: XLD Kabuki syndrome 2 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD

KIF1A 601255

614255: AD Mental retardation, AD 9 614213: AR Neuropathy, hereditary sensory, type IIC

610357: AR Spastic paraplegia 30, AR

Comprehensive Autism Spectrum Disorder AD, AR

KIF1BP 609367 609460: AR Goldberg-Shprintzen megacolon _syndrome Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

KIRREL3 607761 None Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} None

KMT2A 159555 159555: AD Leukemia, myeloid/lymphoid or mixed-lineage

605130: AD Wiedemann-Steiner syndrome

KMT2D 602113 147920: AD Kabuki syndrome 1 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

KRAS 190070

108010: Arteriovenous malformation of the brain, somatic

109800: Bladder cancer, somatic 114480: Breast cancer, somatic

615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic

601626: AD Leukemia, acute myeloid 211980: Lung cancer, somatic 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder

163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

Noonan Syndrome AD KRIT1 604214 116860: AD Cavernous malformations of CNS and retina 116860: AD Cerebral cavernous malformations-1 116860: AD Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations

(20)

Gene MIM No. OMIM Phenotype Neurodevelopment Disease Test Category Inheritance agenesis of 307000: XLR Hydrocephalus due to aqueductal stenosis 307000: XLR Hydrocephalus with Hirschsprung disease

307000: XLR Hydrocephalus with congenital idiopathic intestinal pseudoobstruction 303350: XLR MASA syndrome

L2HGDH 609584 236792: AR L-2-hydroxyglutaric aciduria Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

LAMC3 604349 614115: AR Cortical malformations, occipital Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

LAMP2 309060 300257: XLD Danon disease Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLD

LARGE1 603590

613154: AR Muscular

dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6

608840: AR Muscular

dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6

Microcephaly AR

LAS1L 300964 309585: XLR Wilson-Turner syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

LBR 600024

215140: AR Greenberg skeletal dysplasia 169400: AD Pelger-Huet anomaly 618019: Pelger-Huet anomaly with mild skeletal anomalies

613471: AD ?Reynolds syndrome

LGI1 604619 600512: AD Epilepsy, familial temporal lobe, 1 Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

LIAS 607031 614462: AR Hyperglycinemia, lactic acidosis, _{and seizures} Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

LINS1 610350 614340: AR Mental retardation, AR 27 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

LRP2 600073 222448: AR Donnai-Barrow syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

MAGEL2 605283 615547: AD Schaaf-Yang syndrome Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AD

MAGI2 606382 617609: AR Nephrotic syndrome 15 Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} AR

MAN1B1 604346 614202: AR Mental retardation, AR 15 Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} AR

MAOA 309850 300615: XLR {Antisocial behavior} _{300615: XLR Brunner syndrome} Comprehensive Epilepsy And Autism; _{Comprehensive Autism Spectrum Disorder} XLR

MAP2K1 176872 615279: Cardiofaciocutaneous syndrome 3 Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

Noonan Syndrome None

MAP2K2 601263 615280: Cardiofaciocutaneous syndrome 4 Comprehensive Epilepsy And Autism; Comprehensive Autism Spectrum Disorder;

Noonan Syndrome None

MAPK10 602897 None Comprehensive Epilepsy And Autism; _{Comprehensive Epilepsy; Infantile Epilepsy} None

MBD5 611472 156200: AD Mental retardation, AD 1

AD

MBTPS2 300294

308205: XLR IFAP syndrome with or without BRESHECK syndrome

308800: XLR Keratosis follicularis spinulosa decalvans, XL

300918: XLR ?Olmsted syndrome, XL

MCPH1 607117 251200: AR Microcephaly 1, primary, AR Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Syndromic Epilepsy

MECP2 300005 300496: IC, XL, MF {Autism susceptibility, XL 3}

300673: XLR Encephalopathy, neonatal severe

Comprehensive Epilepsy And Autism; Comprehensive Epilepsy; Infantile Epilepsy; Syndromic Epilepsy And Intellectual Disability;

XLD, XLR, XL, IC, MF

NEURODEVELOPMENT NEXT-GENERATION SEQUENCING PANELS