Human Gene Module / Chromosome 12 / SCN8A

SCN8Asodium channel, voltage gated, type VIII, alpha subunit

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 34
Rare Variants / Common Variants
139 / 0
Aliases
SCN8A, CERIII,  CIAT,  MED,  NaCh6,  Nav1.6,  PN4
Associated Syndromes
Lennox-Gastaut syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
12q13.13
Associated Disorders
ASD, ID, EPS, ADHD, EP, DD/NDD
Relevance to Autism

A rare de novo mutation in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay (Veeramah et al., 2012).

Molecular Function

This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with mental retardation, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.

Reports related to SCN8A (33 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
2 Primary De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Veeramah KR , et al. (2012) No Autism
3 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No Epilepsy, ASD
4 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
5 Positive Association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
6 Recent Recommendation Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Wagnon JL , et al. (2014) No -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No ID, microcephaly
8 Support The phenotypic spectrum of SCN8A encephalopathy. Larsen J , et al. (2015) No -
9 Support De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. Blanchard MG , et al. (2015) No Epilepsy/seizures, ASD
10 Support Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Olson HE , et al. (2015) No Epilepsy
11 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
12 Support Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target? Horvath GA , et al. (2015) No Developmental regression, progressive cerebellar a
13 Support Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Wagnon JL , et al. (2016) No -
14 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
15 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 -
16 Support De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Butler KM , et al. (2016) No ASD, ID
17 Support SCN8A mutation in a child presenting with seizures and developmental delays. Malcolmson J , et al. (2016) No -
18 Support Novel SCN8A mutation in a girl with refractory seizures and autistic features. Jain P (2017) No -
19 Recent Recommendation Regulation of Thalamic and Cortical Network Synchrony by Scn8a. Makinson CD , et al. (2017) No -
20 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
21 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
22 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
23 Support Loss-of-function variants of SCN8A in intellectual disability without seizures. Wagnon JL , et al. (2017) No ADHD, social communication disorder
24 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 Microcephaly
25 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
26 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
27 Support De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy. Epilepsy Genetics Initiative (2017) No DD, epilepsy/seizures
28 Support The phenotype of SCN8A developmental and epileptic encephalopathy. Gardella E , et al. (2018) No -
29 Support Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Liu Y , et al. (2019) Yes -
30 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 -
31 Support The spectrum of intermediate SCN8A-related epilepsy. Johannesen KM , et al. (2019) No ID, ASD or autistic features
32 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes Epilepsy/seizures
33 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort. Callaghan DB , et al. (2019) Yes -
Rare Variants   (139)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>G - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4214C>A p.Ala1405Asp missense_variant De novo NA - 28084268 Jain P (2017)
- p.Ala890Thr missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Asn215Arg missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Phe260Ser missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Ala1650Thr missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Arg1872Gln missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Gln1801Glu missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Ile1479Val missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Ile1605Arg missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
- p.Val1592Leu missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.4296+1del - splice_site_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.2890G>C p.Gly964Arg missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.202A>G p.Ile68Val missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.4423G>A p.Gly1475Arg missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.4859G>T p.Arg1620Leu missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.4865C>A p.Ala1622Asp missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.5280G>A p.Met1760Ile missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.5614C>T p.Arg1872Trp missense_variant De novo NA - 30615093 Liu Y , et al. (2019)
c.752T>C p.Leu251Pro missense_variant De novo NA - 31031587 Xiong J , et al. (2019)
c.5257T>G p.Ser1753Ala missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.1221G>C p.Leu407Phe missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.2549G>A p.Arg850Gln missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.2668G>A p.Ala890Thr missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.2098A>T p.Ile700Leu missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.2415A>G p.Ile805Met missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.4727G>A p.Arg1576Gln missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.4787C>G p.Ser1596Cys missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.4935G>A p.Met1645Ile missense_variant De novo NA - 26544041 Zhang Y , et al. (2015)
c.4394A>T p.Asp1465Val missense_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.1228G>T p.Val410Leu missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.2879T>A p.Val960Asp missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.3076C>T p.Arg1026Cys missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.3097C>G p.Pro1033Ala missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.3148G>A p.Gly1050Ser missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.5879G>A p.Arg1960Gln missense_variant Unknown - - 27875746 Butler KM , et al. (2016)
c.1984C>T p.Arg662Cys missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.4850G>A p.Arg1617Gln missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.5491C>T p.Arg1831Trp missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.5614C>T p.Arg1872Trp missense_variant De novo NA - 25568300 Larsen J , et al. (2015)
c.2932A>G p.Ser978Gly missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.2890G>C p.Gly964Arg missense_variant De novo NA - 28702509 Wagnon JL , et al. (2017)
c.5492G>A p.Arg1831Gln missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.5276A>G p.Asn1759Ser missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
c.1588C>T p.Arg530Trp missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1920C>A p.Asn640Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2130A>C p.Glu710Asp missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5615G>A p.Arg1872Gln missense_variant De novo NA - 26900580 Wagnon JL , et al. (2016)
c.5615G>T p.Arg1872Leu missense_variant De novo NA - 26900580 Wagnon JL , et al. (2016)
c.4423G>A p.Gly1475Arg missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.4948G>A p.Ala1650Thr missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.5491C>T p.Arg1831Trp missense_variant De novo NA - 27864847 Parrini E , et al. (2016)
c.1201T>C p.Tyr401His missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.2549G>T p.Arg850Leu missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.2590C>G p.Leu864Val missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.2932A>G p.Ser978Gly missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.172G>A p.Asp58Asn missense_variant De novo NA - 25725044 Blanchard MG , et al. (2015)
c.-8A>G - 5_prime_UTR_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.3928G>A p.Gly1310Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4051G>A p.Gly1351Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5492G>A p.Arg1831Gln missense_variant De novo NA - 26647175 Horvath GA , et al. (2015)
c.5615G>A p.Arg1872Gln missense_variant De novo NA - 28333917 Vissers LE , et al. (2017)
c.4727G>A p.Arg1576Gln missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.4423G>A p.Gly1475Arg missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.4472C>T p.Ala1491Val missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.4493A>T p.Lys1498Met missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.4594A>T p.Ile1532Phe missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.4639T>G p.Phe1547Val missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.5292C>G p.Ile1764Met missense_variant De novo NA - 30171078 Gardella E , et al. (2018)
c.641G>A p.Gly214Asp missense_variant De novo NA - 27479843 Lelieveld SH , et al. (2016)
c.4877G>A p.Arg1626His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.5302A>G p.Asn1768Asp missense_variant De novo NA - 22365152 Veeramah KR , et al. (2012)
c.2952C>G p.Asn984Lys missense_variant De novo NA - 25725044 Blanchard MG , et al. (2015)
c.4351G>A p.Gly1451Ser missense_variant De novo NA - 25725044 Blanchard MG , et al. (2015)
c.4850G>A p.Arg1617Gln missense_variant De novo NA - 28628100 Geisheker MR , et al. (2017)
c.1915C>T p.Arg639Cys missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4727G>C p.Arg1576Pro missense_variant De novo NA - 30968951 Johannesen KM , et al. (2019)
c.4850G>A p.Arg1617Gln missense_variant De novo NA Simplex 23020937 Rauch A , et al. (2012)
c.1588C>T p.Arg530Trp missense_variant Familial Paternal - 25914188 Olson HE , et al. (2015)
c.3076C>T p.Arg1026Cys missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.3818C>T p.Ala1273Val missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5215C>T p.Pro1739Ser missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.641G>A p.Gly214Asp missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.5458C>T p.Arg1820Ter stop_gained De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.2624T>A p.Leu875Gln missense_variant De novo NA - 23934111 Epi4K Consortium , et al. (2013)
c.3985A>G p.Asn1329Asp missense_variant De novo NA Simplex 27875746 Butler KM , et al. (2016)
c.3995T>G p.Leu1332Arg missense_variant De novo NA Simplex 27875746 Butler KM , et al. (2016)
c.3844G>A p.Ala1282Thr missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.4228G>A p.Ala1410Thr missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5492G>A p.Arg1831Gln missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5507A>G p.Asn1836Ser missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5601G>A p.Gln1867%3D synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2287A>G p.Ile763Val missense_variant De novo NA Multiplex 27875746 Butler KM , et al. (2016)
c.3868C>G p.Leu1290Val missense_variant Familial Paternal - 23708187 Carvill GL , et al. (2013)
c.644A>G p.Asn215Ser missense_variant Familial Maternal - 28628100 Geisheker MR , et al. (2017)
c.800T>C p.Leu267Ser missense_variant De novo NA Simplex 27900360 Malcolmson J , et al. (2016)
c.632T>C p.Val211Ala missense_variant De novo NA - 29121005 Epilepsy Genetics Initiative (2017)
c.667A>G p.Arg223Gly missense_variant De novo NA - 29121005 Epilepsy Genetics Initiative (2017)
c.692T>C p.Ile231Thr missense_variant De novo NA - 29121005 Epilepsy Genetics Initiative (2017)
c.1207G>A p.Val403Met missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.3722A>G p.Tyr1241Cys missense_variant Unknown - Simplex 30968951 Johannesen KM , et al. (2019)
c.4961T>A p.Ile1654Asn missense_variant Unknown - Simplex 30968951 Johannesen KM , et al. (2019)
c.5497G>C p.Asp1833His missense_variant Unknown - Simplex 30968951 Johannesen KM , et al. (2019)
c.5507A>G p.Asn1836Ser missense_variant Unknown - Simplex 30968951 Johannesen KM , et al. (2019)
c.5630A>G p.Asn1877Ser missense_variant Unknown - Simplex 30968951 Johannesen KM , et al. (2019)
c.3652G>A p.Glu1218Lys missense_variant Unknown Not maternal - 28702509 Wagnon JL , et al. (2017)
c.4174A>G p.Lys1392Glu splice_site_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.2287A>G p.Ile763Val missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.3601G>A p.Glu1201Lys missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.3953A>G p.Asn1318Ser missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.3956C>A p.Ala1319Asp missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.3967G>A p.Ala1323Thr missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4423G>A p.Gly1475Arg missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4447G>A p.Glu1483Lys missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4585A>G p.Met1529Val missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4764C>A p.Phe1588Leu missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4764C>G p.Phe1588Leu missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4840A>G p.Thr1614Ala missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4850G>C p.Arg1617Gln missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4850G>C p.Arg1617Pro missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4949C>T p.Ala1650Val missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.5273T>C p.Val1758Ala missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.5311G>A p.Val1771Ile missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.5597G>A p.Arg1866Gln missense_variant De novo NA Simplex 30968951 Johannesen KM , et al. (2019)
c.4300G>A p.Gly1434Arg missense_variant Unknown - Multiplex 30968951 Johannesen KM , et al. (2019)
c.302A>G p.Lys101Arg missense_variant Familial Maternal Simplex 27875746 Butler KM , et al. (2016)
c.1122C>G p.Asn374Lys missense_variant De novo NA Extended multiplex 30968951 Johannesen KM , et al. (2019)
c.2287A>G p.Ile763Val missense_variant De novo NA Extended multiplex 30968951 Johannesen KM , et al. (2019)
c.5630A>G p.Asn1877Ser missense_variant Familial Maternal Multi-generational 27864847 Parrini E , et al. (2016)
c.5630A>G p.Asn1877Ser missense_variant Familial Paternal Multi-generational 27875746 Butler KM , et al. (2016)
c.411C>G p.Ile137Met missense_variant Familial Maternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.2671G>A p.Val891Met missense_variant Familial Maternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.643A>G p.Asn215Asp missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4391T>C p.Ile1464Thr missense_variant Familial Paternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.5615G>A p.Arg1872Gln missense_variant Familial Paternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.5630A>G p.Asn1877Ser missense_variant Familial Paternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.4750G>A p.Gly1584Ser missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2806G>A p.Glu936Lys missense_variant Unknown Not maternal Multi-generational 30968951 Johannesen KM , et al. (2019)
c.1630_1631del p.Asn544SerfsTer38 frameshift_variant Familial Maternal Multi-generational 30968951 Johannesen KM , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD or autistic features (Larsen et al., 2015). A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

Score Delta: Decreased from 3 to 1

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.

10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD or autistic features (Larsen et al., 2015). A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD or autistic features (Larsen et al., 2015). A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD or autistic features (Larsen et al., 2015). A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD or autistic features (Larsen et al., 2015). A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

7/1/2018
4.4 + acc
icon
3

Decreased from 4.4 + acc to 3

Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD. A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

4/1/2018
3
icon
4.4 + acc

Increased from 3 to 4.4 + acc

Description

3

10/1/2017
icon
3

Increased from to 3

Description

Heterozygous mutations in SCN8A are associated with multiple disorders, including early infantile epileptic encephalopathy (OMIM 614558), benign familial infantile seizures (OMIM 617080), and cognitive impairment with or without cerebellar ataxia (OMIM 614306); in some cases, individuals with one of these disorders also present with ASD. A rare de novo missense variant in the SCN8A gene was found in a patient with epilepsy, autism, intellectual disability and developmental delay in Veeramah et al., 2012; functional analysis of this variant was consistent with a gain-of-function phenotype in this patient, and mice that were heterozygous for this variant (Scn8aN1768D/+) exhibited seizures, SUDEP, and mild impairments in motor coordination and social discrimination (Wagnon et al., 2014). De novo missense variants in SCN8A have been identified in individuals presenting with ASD and intellectual disability in the presence or absence of seizures (Blanchard et al., 2015; Bowling et al., 2017). Potentially damaging missense variants in SCN8A have been identified in ASD probands in several additional studies (Butler et al., 2017; Geisheker et al., 2017; Li et al., 2017).

Krishnan Probability Score

Score 0.58519450270649

Ranking 529/25841 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 0.99999829029275

Ranking 340/18225 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
Sanders TADA Score

Score 0.94245329211243

Ranking 15312/18665 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).
Larsen Cumulative Evidence Score

Score 9

Ranking 213/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.31666331421538

Ranking 2493/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Scnm1-ps sodium channel modifier 1, pseudogene Mouse Direct Regulation 69269 Q8K136
Submit New Gene

Report an Error

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.
Close