Human Gene Module / Chromosome 19 / ATP1A3

ATP1A3ATPase Na+/K+ transporting subunit alpha 3

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 26
Rare Variants / Common Variants
58 / 0
Aliases
ATP1A3, AHC2,  CAPOS,  DYT12,  RDP
Associated Syndromes
CAPOS syndrome
Chromosome Band
19q13.2
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Molecular Function

The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. This gene encodes an alpha 3 catalytic subunit. Heterozygous variants in ATP1A3 are responsible for alternating hemiplegia of childhood 2 (AHC2; OMIM 614820) and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM 601338).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ATP1A3 (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary A novel recurrent mutation in ATP1A3 causes CAPOS syndrome Demos MK , et al. (2014) No ASD
2 Support ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients Yang X , et al. (2014) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients Panagiotakaki E , et al. (2015) No -
5 Recent Recommendation Deficits in social behavioral tests in a mouse model of alternating hemiplegia of childhood Kirshenbaum GS , et al. (2016) No -
6 Support A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia Smedemark-Margulies N , et al. (2016) No -
7 Support Mosaicism in ATP1A3-related disorders: not just a theoretical risk Hully M , et al. (2016) No Epilepsy/seizures, autistic features
8 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No -
9 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Epileptic encephalopathy, stereotypies
10 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
11 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) No -
12 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
13 Support De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome Torres A , et al. (2018) Yes -
14 Support Mutational and phenotypic expansion of ATP1A3-related disorders: Report of nine cases Boonsimma P et al. (2020) No ID, epilepsy/seizures, rapid-onset dystonia-parkin
15 Support - Kwong AK et al. (2021) No -
16 Support - Brunet T et al. (2021) No -
17 Recent Recommendation - Miyatake S et al. (2021) No ID
18 Support - Valentino F et al. (2021) No Epilepsy/seizures
19 Support - Jiang Y et al. (2021) Yes -
20 Support - Woodbury-Smith M et al. (2022) Yes -
21 Support - Zhou X et al. (2022) Yes -
22 Support - Calame DG et al. (2023) No ASD or autistic features, ADHD, epilepsy/seizures
23 Support - Alyamani SA et al. (2023) No Autistic features, ID
24 Support - Sanchis-Juan A et al. (2023) No ID
25 Support - Luigi Vetri et al. (2024) No -
26 Support - Axel Schmidt et al. (2024) No ID, epilepsy/seizures
Rare Variants   (58)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1253C>T p.Ser418Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2497G>A p.Asp833Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.948C>T p.Leu316%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.499A>G p.Met167Val missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.954C>G p.Tyr318Ter missense_variant De novo - - 33446253 Kwong AK et al. (2021)
c.2224G>T p.Asp742Tyr missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.449C>T p.Ser150Phe missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.2041G>A p.Ala681Thr missense_variant De novo - - 29922587 Torres A , et al. (2018)
c.410C>A p.Ser137Tyr missense_variant Unknown - - 32339621 Boonsimma P et al. (2020)
c.2263G>T p.Gly755Cys missense_variant Unknown - - 32339621 Boonsimma P et al. (2020)
c.2401G>A p.Asp801Asn missense_variant De novo - - 32339621 Boonsimma P et al. (2020)
c.2401G>A p.Asp801Asn missense_variant Unknown - - 32339621 Boonsimma P et al. (2020)
c.2425G>C p.Ala809Pro missense_variant De novo - - 32339621 Boonsimma P et al. (2020)
c.2429T>G p.Ile810Ser missense_variant De novo - - 32339621 Boonsimma P et al. (2020)
c.2479A>T p.Arg827Trp missense_variant De novo - - 32339621 Boonsimma P et al. (2020)
c.2552A>C p.Gln851Pro missense_variant De novo - - 32339621 Boonsimma P et al. (2020)
c.2600G>T p.Gly867Val missense_variant Unknown - - 32339621 Boonsimma P et al. (2020)
c.2116G>A p.Glu706Lys missense_variant De novo - - 34356170 Valentino F et al. (2021)
c.2300G>A p.Arg767His missense_variant De novo - - 37482377 Alyamani SA et al. (2023)
c.2440G>A p.Gly814Ser missense_variant De novo - - 37482377 Alyamani SA et al. (2023)
c.926T>C p.Phe309Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.773G>A p.Arg258Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1756C>G p.Leu586Val missense_variant Familial - - 38256219 Luigi Vetri et al. (2024)
c.2116G>C p.Glu706Gln missense_variant Familial - - 38256219 Luigi Vetri et al. (2024)
c.2266C>T p.Arg756Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2312C>T p.Thr771Ile missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2497G>A p.Asp833Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.266G>C p.Gly89Ala missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2452G>A p.Asp818Asn missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.2443G>A p.Glu815Lys missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2266C>T p.Arg756Cys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2324C>T p.Pro775Leu missense_variant De novo - Simplex 37043503 Calame DG et al. (2023)
c.2324C>T p.Pro775Leu missense_variant Unknown - Simplex 37043503 Calame DG et al. (2023)
c.2116G>A p.Glu706Lys missense_variant De novo - Multiplex 27726050 Hully M , et al. (2016)
c.2266C>T p.Arg756Cys missense_variant De novo - Multiplex 27726050 Hully M , et al. (2016)
c.1765G>T p.Val589Leu missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.1787G>A p.Cys596Tyr missense_variant De novo - Simplex 33762331 Miyatake S et al. (2021)
c.2684A>C p.Gln895Pro missense_variant De novo - Simplex 33762331 Miyatake S et al. (2021)
c.998T>A p.Val333Asp missense_variant De novo - Simplex 37482377 Alyamani SA et al. (2023)
c.1198G>A p.Glu400Lys missense_variant De novo - Simplex 37482377 Alyamani SA et al. (2023)
c.2284G>T p.Gly762Cys missense_variant De novo - Simplex 37482377 Alyamani SA et al. (2023)
c.2434G>A p.Asp812Asn missense_variant De novo - Simplex 37482377 Alyamani SA et al. (2023)
c.2435A>T p.Asp812Val missense_variant De novo - Simplex 37482377 Alyamani SA et al. (2023)
c.2715C>T p.Tyr905%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2201G>A p.Gly734Glu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2363C>T p.Pro788Leu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2440G>A p.Asp814Asn missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.385G>A p.Val129Met missense_variant De novo - - 27626066 Smedemark-Margulies N , et al. (2016)
c.2570_2572del p.Phe857del inframe_deletion De novo - Simplex 33762331 Miyatake S et al. (2021)
c.2976_2978del p.Asp992del inframe_deletion De novo - Simplex 33762331 Miyatake S et al. (2021)
c.2324C>T p.Pro775Leu missense_variant Unknown Not maternal Simplex 37043503 Calame DG et al. (2023)
c.2560_2568del p.Gly854_Phe856del inframe_deletion De novo - Simplex 33762331 Miyatake S et al. (2021)
c.746del p.Asn249ThrfsTer97 frameshift_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1081_1086del p.Asn361_Leu362del inframe_deletion Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2446G>A p.Asp816Asn missense_variant Familial Maternal Multi-generational 24468074 Demos MK , et al. (2014)
c.2452G>A p.Asp818Asn missense_variant Familial Paternal Multi-generational 24468074 Demos MK , et al. (2014)
c.3008_3009insACGAAATCC p.Asp1003delinsGluArgAsnPro inframe_insertion De novo - Simplex 33762331 Miyatake S et al. (2021)
c.2972_2982delinsTTGCGCATCTTCATCTG p.Tyr991_Ile994delinsPheAlaHisLeuHisLeu inframe_indel De novo - Simplex 33762331 Miyatake S et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

4/1/2021
3S
icon
3S

Decreased from 3S to 3S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[Exome sequencing in paediatric patients with movement disorders2021] [De novo ATP1A3 variants cause polymicrogyria2021]
1/1/2021
3S
icon
3S

Decreased from 3S to 3S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
7/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[Mutational and phenotypic expansion of ATP1A3-related disorders: Report of nine cases2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[New Scoring Scheme]
7/1/2018
S
icon
4S

Increased from S to 4S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016). A second de novo missense variant that was predicted to be damaging was observed in an ASD proband from a Japanese trio in Takata et al., 2018. TADA analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified ATP1A3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Reports Added
[De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-well...2018]
10/1/2017
S
icon
S

Increased from S to S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016).

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
7/1/2017
S
icon
S

Increased from S to S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
10/1/2016
S
icon
S

Increased from S to S

Description

Two siblings from a British family with CAPOS syndrome and a p.Glu818Lys missense variant in ATP1A3 were diagnosed with autism spectrum disorder; this variant was also observed in two additional families with CAPOS syndrome in the absence of ASD (Demos et al., 2014). A probably damaging missense variant in ATP1A3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Evaluation of the social behavior of the Myshkin mouse model of AHC2, which has an p.Ile810Asn mutation identical to one found in several AHC2 patients, including one patient with co-morbid autism (Yang et al., 2014; Panagiotakaki et al., 2015), identified deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test (Kirshenbaum et al., 2016).

Reports Added
[A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia.2016] [Mosaicism in ATP1A3-related disorders: not just a theoretical risk.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
Krishnan Probability Score

Score 0.57047086654759

Ranking 918/25841 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.
Original Source
ExAC Score

Score 0.99999432301788

Ranking 410/18225 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
Original Source
Sanders TADA Score

Score 0.84735495933891

Ranking 3370/18665 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).
Original Source
Zhang D Score

Score 0.2352157467055

Ranking 3682/20870 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.
Original Source
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