Human Gene Module / Chromosome 2 / SCN1A

SCN1Asodium channel, voltage-gated, type I, alpha subunit

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
24 / 64
Rare Variants / Common Variants
178 / 2
Aliases
SCN1A, Na(v)1.1, FEB3,  NAC1,  SCN1,  SMEI,  HBSCI,  GEFSP2,  Nav1.1
Associated Syndromes
Dravet syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
2q24.3
Associated Disorders
EPS, ADHD, EP, ID, ASD, DD/NDD
Relevance to Autism

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018). Additional de novo missense variants in the SCN1A gene were identified in novel ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis in this report identified SCN1A as a candidate gene with a false discovery rate < 0.1.

Molecular Function

This gene encodes the large alpha subunit of the vertebrate voltage-gated sodium channel essential for the generation and propagation of action potentials, mainly in nerve and muscle.

Reports related to SCN1A (64 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS. Escayg A , et al. (2000) No -
2 Highly Cited De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Claes L , et al. (2001) No -
3 Primary Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Weiss LA , et al. (2003) Yes -
4 Support Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy. Ohmori I , et al. (2006) No -
5 Recent Recommendation Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Wolff M , et al. (2006) No -
6 Recent Recommendation Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation. Osaka H , et al. (2007) No Asperger syndrome
7 Recent Recommendation Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mu... Ogiwara I , et al. (2007) No -
8 Support Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O'Roak BJ , et al. (2011) Yes -
9 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
10 Support Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures. Shi YW , et al. (2011) No -
11 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
12 Support SCN1A mutation associated with intractable myoclonic epilepsy and migraine headache. Frosk P , et al. (2012) No Epilepsy, ASD
13 Support Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome. Kwong AK , et al. (2012) No ASD, ID
14 Recent Recommendation Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression. Thompson CH , et al. (2012) No -
15 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
16 Support Generalized epilepsy with febrile seizure plus (GEFS) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient. Tan EH , et al. (2012) No DD, ID
17 Recent Recommendation SCN1A testing for epilepsy: application in clinical practice. Hirose S , et al. (2013) No -
18 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
19 Positive Association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
20 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Toma C , et al. (2013) Yes -
21 Positive Association Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A. Kasperaviciute D , et al. (2013) No -
22 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
23 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
24 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
25 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
26 Recent Recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load. Jiang Y , et al. (2015) No -
27 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
28 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
29 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
30 Recent Recommendation CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation. Liu J , et al. (2016) No -
31 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
32 Support The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies. Schuch JB , et al. (2016) No -
33 Support A Point Mutation in SCN1A 5' Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by... Gao QW , et al. (2016) No -
34 Support Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy. Fry AE , et al. (2016) No -
35 Support Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Riazuddin S , et al. (2016) No -
36 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
37 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
38 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No -
39 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No Dravet syndrome
40 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
41 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
42 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
43 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
44 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No -
45 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
46 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Tumien B , et al. (2017) No Developmental regression
47 Support Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. de Lange IM , et al. (2018) No DD/ID, ASD, ADHD
48 Support Language Regression in an Atypical SLC6A1 Mutation. Islam MP , et al. (2018) Yes Language delay, regression
49 Support Clinical genome sequencing in an unbiased pediatric cohort. Thiffault I , et al. (2018) No DD, epilepsy/seizures
50 Support First report on the association of SCN1A mutation, childhood schizophrenia and autism spectrum disorder without epilepsy. Papp-Hertelendi R , et al. (2018) Yes -
51 Recent Recommendation Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies. Carvill GL , et al. (2018) No -
52 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
53 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No ID
54 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes Dravet syndrome
55 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Autistic features, stereotypies
56 Support Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients. Balicza P , et al. (2019) Yes Dravet syndrome
57 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
58 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability. Borlot F , et al. (2019) No Autistic features
59 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
60 Support Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A. Steward CA , et al. (2019) No -
61 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism. Breuss MW , et al. (2019) Yes -
62 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
63 Support Utility of clinical exome sequencing in a complex Emirati pediatric cohort Mahfouz NA et al. (2020) No -
64 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes ID, epilepsy/seizures
Rare Variants   (178)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo NA - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo NA - 27113213 Fry AE , et al. (2016)
c.79G>A - - De novo NA Simplex 31814998 Steward CA , et al. (2019)
c.301G>A - - De novo NA Simplex 31814998 Steward CA , et al. (2019)
- - copy_number_loss De novo NA - 29460957 de Lange IM , et al. (2018)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
G>A p.? splice_site_variant De novo NA - 11359211 Claes L , et al. (2001)
- - copy_number_loss De novo NA Simplex 30526861 Carvill GL , et al. (2018)
c.4096G>A p.Val1366Ile missense_variant - - - 17507202 Osaka H , et al. (2007)
c.2624C>T p.Thr875Met missense_variant - - - 10742094 Escayg A , et al. (2000)
c.3299insAA - frameshift_variant De novo NA - 11359211 Claes L , et al. (2001)
c.4943G>A p.Arg1648His missense_variant - - - 10742094 Escayg A , et al. (2000)
c.5864T>C p.Ile1955Thr missense_variant - - - 12610651 Weiss LA , et al. (2003)
c.1333C>T p.Gln445Ter stop_gained De novo NA - 30945278 Jiao Q , et al. (2019)
c.79A>C p.Arg27= missense_variant De novo NA - 31139143 Long S , et al. (2019)
c.664C>T p.Arg222Ter stop_gained De novo NA - 11359211 Claes L , et al. (2001)
c.1053T>A p.Cys351Ter stop_gained Unknown - - 22848613 Kwong AK , et al. (2012)
c.3733C>T p.Arg1245Ter stop_gained De novo NA - 30945278 Jiao Q , et al. (2019)
c.-159_-156del - frameshift_variant De novo NA - 31139143 Long S , et al. (2019)
c.569G>A p.Trp190Ter stop_gained De novo NA - 22848613 Kwong AK , et al. (2012)
CTG>C - frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.603-2A>G - splice_site_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.3969+2451G>C - intron_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.5148C>A p.Cys1716Ter stop_gained De novo NA - 31031587 Xiong J , et al. (2019)
c.2589+3A>T - intron_variant De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.1348C>T p.Gln450Ter stop_gained De novo NA - 22848613 Kwong AK , et al. (2012)
c.2214G>A p.Trp738Ter stop_gained De novo NA - 22848613 Kwong AK , et al. (2012)
c.301C>T p.Arg101Trp missense_variant De novo NA - 27113213 Fry AE , et al. (2016)
c.302G>A p.Arg101Gln missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.524C>T p.Ala175Val missense_variant De novo NA - 31139143 Long S , et al. (2019)
c.668C>T p.Ala223Val missense_variant De novo NA - 31139143 Long S , et al. (2019)
c.4243T>C p.Phe1415Leu missense_variant Unknown - - 31139143 Long S , et al. (2019)
c.277T>C p.Leu93= missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.945G>A p.Lys315= missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.2214dup p.Tyr739ValfsTer2 intron_variant Unknown - - 32477112 Lee J et al. (2020)
c.2923C>T p.Leu975Phe missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.275T>G p.Val92Gly missense_variant De novo NA - 31273778 Borlot F , et al. (2019)
c.1390G>C p.Ala464Pro missense_variant Unknown - - 22848613 Kwong AK , et al. (2012)
c.1546G>A p.Asp516Asn missense_variant Unknown - - 22848613 Kwong AK , et al. (2012)
c.3637C>T p.Arg1213Ter stop_gained De novo NA - 28554332 Bowling KM , et al. (2017)
c.179A>G p.Asn60Ser missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.5197A>G p.Ile1733Val missense_variant De novo NA - 23248692 Tan EH , et al. (2012)
c.5005G>A p.Ala1669Thr missense_variant De novo NA - 27113213 Fry AE , et al. (2016)
c.3620T>C p.Leu1207Pro missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.5315C>G p.Ala1772Gly missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.2956C>T p.Leu986Phe missense_variant De novo NA - 11359211 Claes L , et al. (2001)
c.311C>T p.Ala104Val missense_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.5171C>T p.Ala1724Val missense_variant Unknown - - 31273778 Borlot F , et al. (2019)
c.602+1G>A - splice_site_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.650C>T p.Thr217Ile missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
- - copy_number_loss Unknown Not maternal Simplex 30526861 Carvill GL , et al. (2018)
c.5726C>T p.Thr1909Ile missense_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.1177C>A p.Arg393Ser missense_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.1264G>A p.Val422Met missense_variant De novo NA - 22848613 Kwong AK , et al. (2012)
A>G p.Phe408Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1852C>T p.Arg618Cys missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.2917A>G p.Met973Val missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.4878_4880del p.Lys1627del inframe_indel De novo NA - 30945278 Jiao Q , et al. (2019)
c.2220A>T p.Lys740Asn splice_site_variant De novo NA - 31139143 Long S , et al. (2019)
c.2116G>T p.Asp706Tyr stop_gained De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.2134C>T p.Arg712Ter stop_gained De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.3641T>G p.Ile1214Arg missense_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.3607C>T p.Gln1203Ter stop_gained Unknown - Unknown 31130284 Monies D , et al. (2019)
c.1177C>T p.Arg393Cys missense_variant De novo NA - 31873310 Breuss MW , et al. (2019)
c.5195C>T p.Pro1732Leu missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.4002+2451G>C - intron_variant De novo NA Simplex 30526861 Carvill GL , et al. (2018)
c.265-19T>C - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.602+1G>A - splice_site_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.2248T>C p.Cys750Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3733C>T p.Arg1245Ter stop_gained De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.4547C>A p.Ser1516Ter stop_gained De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.4814A>T p.Asn1605Ile missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.4934G>A p.Arg1645Gln missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.4934G>A p.Arg1645Gln missense_variant De novo NA - 31134136 Balicza P , et al. (2019)
c.664C>T p.Arg222Ter stop_gained De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5538G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.980T>G p.Leu327Arg missense_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.4020T>G p.Leu1340= missense_variant De novo NA - 30008475 Thiffault I , et al. (2018)
c.3308T>C p.Met1103Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5449C>T p.Pro1817Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.32C>A p.Pro11His missense_variant De novo NA Simplex 28940097 Anazi S , et al. (2017)
c.3977C>T p.Ala1326Val missense_variant De novo NA - 23708187 Carvill GL , et al. (2013)
c.4033C>T p.Pro1345Ser missense_variant De novo NA - 23708187 Carvill GL , et al. (2013)
c.4453A>G p.Asn1485Asp missense_variant De novo NA - 23708187 Carvill GL , et al. (2013)
c.254T>A p.Ile85Asn missense_variant De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.677C>T p.Thr226Met missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.4002+2455G>A - intron_variant Unknown Not maternal - 30526861 Carvill GL , et al. (2018)
c.4002+2168_4002+2172del - intron_variant De novo NA - 30526861 Carvill GL , et al. (2018)
c.4926G>C p.Arg1642Ser missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.5348C>T p.Ala1783Val missense_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.3637C>T p.Arg1213Ter stop_gained De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.2824C>G p.Leu942Val missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.5797C>T p.Arg1933Ter stop_gained Familial Paternal - 31452935 Feliciano P et al. (2019)
c.1132del p.Leu378Ter frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.4834G>A p.Val1612Ile missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.5111T>C p.Ile1704Thr missense_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.5161A>T p.Thr1721Ser missense_variant Familial Paternal - 30945278 Jiao Q , et al. (2019)
c.2118del p.Pro707LeufsTer8 frameshift_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.310G>C p.Ala104Pro missense_variant De novo NA Simplex 31130284 Monies D , et al. (2019)
c.3587T>C p.Leu1196Pro missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.3412del p.Leu1138TrpfsTer8 frameshift_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.4096G>A p.Val1366Ile missense_variant Familial Maternal - 17507202 Osaka H , et al. (2007)
c.4942C>T p.Arg1648Cys missense_variant De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.2378C>T p.Thr793Met missense_variant Familial Maternal - 22848613 Kwong AK , et al. (2012)
c.1757C>T p.Ser586Phe missense_variant Familial Paternal - 29961511 Islam MP , et al. (2018)
c.5314G>A p.Ala1772Thr missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5315C>T p.Ala1772Val missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4698T>C p.Ser1566= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2189T>G;c.2097T>G - 2KB_upstream_variant Familial Maternal - 26969601 Gao QW , et al. (2016)
c.4834G>A p.Val1612Ile missense_variant Familial Maternal - 22848613 Kwong AK , et al. (2012)
NM_001165963:IVS3+3A>C p.? splice_site_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.1006T>G p.Cys336Gly missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.1177C>T p.Arg393Cys missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.2876G>A p.Cys959Tyr missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.253_254del p.Ile85GlnfsTer2 frameshift_variant De novo NA - 11359211 Claes L , et al. (2001)
c.4229del p.Asn1410MetfsTer2 frameshift_variant De novo NA - 22848613 Kwong AK , et al. (2012)
NM_001165963:IVS21+1G>A p.? splice_site_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.5714C>T p.Pro1905Leu missense_variant De novo NA Simplex 21572417 O'Roak BJ , et al. (2011)
c.5714C>T p.Pro1905Leu missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.5779C>T p.Arg1927Gly missense_variant De novo NA Simplex 23160955 O'Roak BJ , et al. (2012)
c.1209del p.Phe403LeufsTer12 frameshift_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.4612G>A p.Val1538Ile missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.4529C>A p.Ala1510Glu missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.5222G>C p.Cys1741Ser missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.2729A>G p.Gln910Arg missense_variant Unknown Not maternal - 31273778 Borlot F , et al. (2019)
c.4558del p.Gln1520LysfsTer19 frameshift_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.568T>C p.Trp190Arg missense_variant Unknown Not maternal - 27864847 Parrini E , et al. (2016)
c.3320dup p.Asn1107LysfsTer17 frameshift_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.4836del p.Ile1613PhefsTer5 frameshift_variant De novo NA - 23708187 Carvill GL , et al. (2013)
c.3672del p.Ile1224MetfsTer4 frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.587del p.Thr196MetfsTer20 frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.1261G>A p.Val421Met missense_variant De novo NA Simplex 27848944 Trujillano D , et al. (2016)
c.3931G>A p.Ala1311Thr missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.4834G>A p.Val1612Ile missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.200_203del p.Asp67ValfsTer24 splice_site_variant De novo NA - 29286531 Tumien B , et al. (2017)
c.4757del p.Gly1586GlufsTer5 frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.1876A>G p.Ser626Gly missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.5103_5106del p.Ile1701MetfsTer13 frameshift_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.285_286insAGAA p.Gly96ArgfsTer24 frameshift_variant De novo NA - 27113213 Fry AE , et al. (2016)
c.5119_5122del p.Phe1707ArgfsTer7 frameshift_variant De novo NA - 11359211 Claes L , et al. (2001)
c.218_252del p.Val73AspfsTer3 frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.5503C>T p.Leu1835Phe missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.4574_4577del p.Arg1525GlnfsTer13 frameshift_variant De novo NA - 11359211 Claes L , et al. (2001)
c.3402_3403del p.Ser1134ArgfsTer13 frameshift_variant De novo NA - 31031587 Xiong J , et al. (2019)
c.3521C>G p.Thr1174Ser missense_variant Familial Maternal Simplex 22550089 Frosk P , et al. (2012)
c.4061del p.Cys1354PhefsTer6 frameshift_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.4411T>C p.Ser1471Pro missense_variant Familial Paternal Multiplex 22151702 Shi YW , et al. (2011)
c.3497A>C p.Gln1166Pro missense_variant Familial Paternal Multiplex 23999528 Toma C , et al. (2013)
c.3000del p.Ala1001GlnfsTer9 frameshift_variant De novo NA Simplex 26544041 Zhang Y , et al. (2015)
c.1076A>C p.Asn359Thr missense_variant Familial Unknown Unknown 23708187 Carvill GL , et al. (2013)
NM_001202435.3:c.3430_3C>G p.? splice_site_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.4793A>T p.Tyr1598Phe missense_variant Unknown - Simplex 30060894 Papp-Hertelendi R , et al. (2018)
c.1625G>A p.Arg542Gln missense_variant Familial Paternal Multiplex 12610651 Weiss LA , et al. (2003)
c.4384_4385del p.Tyr1462LeufsTer23 frameshift_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.983_984insC p.Glu328AspfsTer12 frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.2971_2972delinsG p.Leu991ValfsTer2 frameshift_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.3101T>C p.Ile1034Thr missense_variant Familial Paternal Multiplex 12610651 Weiss LA , et al. (2003)
c.3112T>C p.Phe1038Leu missense_variant Familial Paternal Multiplex 12610651 Weiss LA , et al. (2003)
c.3890_3903del p.Val1297GlufsTer30 frameshift_variant De novo NA - 29460957 de Lange IM , et al. (2018)
c.3905dup p.Asn1302LysfsTer30 frameshift_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.4002+2165C>T - intron_variant Familial Paternal Multi-generational 30526861 Carvill GL , et al. (2018)
c.4002+2503C>T - intron_variant Familial Maternal Multi-generational 30526861 Carvill GL , et al. (2018)
c.3562delinsCC p.Arg1188ProfsTer29 frameshift_variant Familial Paternal - 30945278 Jiao Q , et al. (2019)
c.248A>G p.Tyr83Cys missense_variant Familial Maternal Multi-generational 30945278 Jiao Q , et al. (2019)
c.1811G>A p.Arg604His missense_variant Familial Maternal Simplex 26845707 Alvarez-Mora MI , et al. (2016)
c.393C>G p.Ser131Arg missense_variant Familial Maternal Multi-generational 27113213 Fry AE , et al. (2016)
c.5768A>G p.Gln1923Arg missense_variant Familial Paternal Multi-generational 22151702 Shi YW , et al. (2011)
c.133G>A p.Asp45Asn missense_variant Familial Paternal Multi-generational 23708187 Carvill GL , et al. (2013)
c.1848G>C p.Glu616Asp missense_variant Familial Maternal Multi-generational 27864847 Parrini E , et al. (2016)
c.2862+1G>T;c.2913+1G>T;c.2946+1G>T p.? splice_site_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5119_5122del p.Phe1707ArgfsTer7 frameshift_variant Unknown - Extended multiplex 32382396 Mahfouz NA et al. (2020)
c.4319C>T p.Pro1440Leu missense_variant Unknown - Multiplex or multi-generational 26637798 D'Gama AM , et al. (2015)
c.5732T>G p.Ile1911Ser missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5501C>T p.Ala1834Val missense_variant Familial Both parents Extended multiplex 27457812 Riazuddin S , et al. (2016)
c.5962C>T p.Arg1988Trp missense_variant Familial Paternal and maternal Multi-generational 23708187 Carvill GL , et al. (2013)
c.2050C>T;c.2101C>T;c.2134C>T p.Arg684Ter;p.Arg701Ter;p.Arg712Ter stop_gained De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.2629G>C;c.2680G>C;c.2713G>C p.Ala877Pro;p.Ala894Pro;p.Ala905Pro missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5234C>A;c.5285C>A;c.5318C>A p.Ser1745Tyr;p.Ser1762Tyr;p.Ser1773Tyr missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.264+3440A>G - intron_variant - - - 24014518 Kasperaviciute D , et al. (2013)
c.-142+26807G>T Minor allele, A intron_variant - - - 24014518 Kasperaviciute D , et al. (2013)
SFARI Gene score
1

High Confidence

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018).

Score Delta: Score remained at 3S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2020
3S
icon
3S

Score remained at 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018).

1/1/2020
3S
icon
3S

Score remained at 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018).

10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018).

7/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017). Assessment of a cohort of 35 individuals with Dravet syndrome using standardized tools demonstrated that 11 patients (39%) had ASD according to the DSM5 classification and ADIR and ADOS2 (Ouss et al., 2018).

4/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

1/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

10/1/2018
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

7/1/2018
4.4 + acc2 + S
icon
3S

Decreased from 4.4 + acc2 + S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

10/1/2017
3S
icon
3S

Increased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

7/1/2017
3S
icon
3S

Increased from 3S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

4/1/2017
S
icon
3S

Increased from S to 3S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.). De novo variants in SCN1A, including multiple missense variants that were predicted to be damaging and one likely gene-disruptive variant, have been identified in ASD probands (O'Roak et al., 2011; O'Roak et al., 2012; O'Roak et al., 2012; De Rubeis et al., 2014; Yuen et al., 2017)

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [SCN1A mutation associated with intractable myoclonic epilepsy and migraine headache.2012] [Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS.2000] [De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.2001] [Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation.2007] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Generalized epilepsy with febrile seizure plus (GEFS) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.2013] [Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings.2006] [Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mu...2007] [Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.2012] [SCN1A testing for epilepsy: application in clinical practice.2013] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures.2011] [CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation.2016] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies.2016] [A Point Mutation in SCN1A 5' Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by...2016] [Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.2016] [Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

10/1/2016
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

7/1/2016
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

4/1/2016
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [SCN1A mutation associated with intractable myoclonic epilepsy and migraine headache.2012] [Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS.2000] [De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.2001] [Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation.2007] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Generalized epilepsy with febrile seizure plus (GEFS) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.2013] [Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings.2006] [Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mu...2007] [Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.2012] [SCN1A testing for epilepsy: application in clinical practice.2013] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures.2011] [CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation.2016] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies.2016] [A Point Mutation in SCN1A 5' Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by...2016] [Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.2016]
1/1/2016
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [SCN1A mutation associated with intractable myoclonic epilepsy and migraine headache.2012] [Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS.2000] [De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.2001] [Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation.2007] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Generalized epilepsy with febrile seizure plus (GEFS) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.2013] [Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings.2006] [Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mu...2007] [Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.2012] [SCN1A testing for epilepsy: application in clinical practice.2013] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Mosaic SCN1A mutations in familial partial epilepsy with antecedent febrile seizures.2011] [CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation.2016] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies.2016]
7/1/2015
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

Reports Added
[Sodium channels SCN1A, SCN2A and SCN3A in familial autism.2003] [Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.2011] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [SCN1A mutation associated with intractable myoclonic epilepsy and migraine headache.2012] [Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS.2000] [De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.2001] [Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation.2007] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Generalized epilepsy with febrile seizure plus (GEFS) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.2013] [Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings.2006] [Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mu...2007] [Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.2012] [SCN1A testing for epilepsy: application in clinical practice.2013] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Incorporating Functional Information in Tests of Excess De Novo Mutational Load.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Mutations appear to give rise to Dravet Syndrome as well as distinct epilepsy-related disorders and also migraine. Missense mutations were observed in cases from multiple unrelated families, one of which presented with seizures and Asperger Syndrome (asymptomatic carriers were also seen in families, but missense variants were not observed in any of 304 controls (Osaka H et al.). Autism seems to be common amongst individuals with Dravet Syndrome but the report does not give a frequency for the 20 individuals studied (Wolff M et al.). Rare missense variants were observed in 4/299 AGRE families but none of 96 controls, and one of these variants was found previously in a child with juvenile myoclonic epilepsy (Weiss LA et al.).

Krishnan Probability Score

Score 0.50669698524454

Ranking 1880/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999999953539

Ranking 87/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.957

Ranking 76/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.12693194285863

Ranking 76/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.11455033178404

Ranking 5831/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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