Human Gene Module / Chromosome 1 / AHDC1

AHDC1AT-hook DNA binding motif containing 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
10 / 32
Rare Variants / Common Variants
108 / 0
EAGLE Score
14.25
Strong Learn More
Aliases
AHDC1, MRD25
Associated Syndromes
Xia-Gibbs syndrome, Xia-Gibbs syndrome, DD, ID, Xia-Gibbs syndrome, ASD, Xia-Gibbs syndrome, DD, Xia-Gibbs syndrome, ASD, ADHD, DD, ID
Chromosome Band
1p36.11-p35.3
Associated Disorders
DD/NDD, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Molecular Function

This gene encodes a protein containing two AT-hooks, which likely function in DNA binding. Mutations in this gene were found in individuals with Xia-Gibbs syndrome (OMIM 615829), a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea (Xia et al., 2014).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AHDC1 (32 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea Xia F , et al. (2014) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus Quintero-Rivera F , et al. (2015) Yes Congenital heart defects
4 Recent Recommendation De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay Yang H , et al. (2016) No ASD
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
7 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
8 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
9 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Behavioral anomalies, microcephaly
10 Recent Recommendation The phenotypic spectrum of Xia-Gibbs syndrome Jiang Y , et al. (2018) No ASD
11 Support Variable Clinical Manifestations of Xia-Gibbs syndrome: Findings of Consecutively Identified Cases at a Single Children's Hospital Ritter AL , et al. (2018) No ASD
12 Support Xia-Gibbs syndrome in adulthood: a case report with insight into the natural history of the condition Murdock DR , et al. (2019) No -
13 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
14 Support - Khayat MM et al. (2021) No ASD, epilepsy/seizures
15 Support - Della Vecchia S et al. (2021) Yes DD, epilepsy/seizures
16 Support - Pode-Shakked B et al. (2021) No Epilepsy/seizures
17 Support - Xie Y et al. (2021) No ASD
18 Support - Woodbury-Smith M et al. (2022) Yes -
19 Support - Brea-Fernández AJ et al. (2022) No -
20 Support - Danda S et al. (2022) No Autistic features, stereotypy, epilepsy/seizures
21 Support - Carvalho LML et al. (2022) Yes -
22 Support - Romano F et al. (2022) No ASD, ADHD, epilepsy/seizures
23 Support - Levchenko O et al. (2022) No -
24 Support - Zhou X et al. (2022) Yes -
25 Support - Yuan B et al. (2023) Yes -
26 Support - Spataro N et al. (2023) No Epilepsy/seizures, autistic features
27 Support - Sanchis-Juan A et al. (2023) No -
28 Support - M Cecilia Poli et al. () No -
29 Support - Tamam Khalaf et al. (2024) No -
30 Support - Axel Schmidt et al. (2024) No Stereotypy
31 Support - Paola Granata et al. (2024) Yes -
32 Support - Burcu KardaÅŸ et al. (2025) Yes -
Rare Variants   (108)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 30152016 Ritter AL , et al. (2018)
c.1759C>T p.Arg587Ter stop_gained De novo - - 28135719 et al. (2017)
c.2188G>T p.Glu730Ter stop_gained De novo - - 28135719 et al. (2017)
c.2773C>T p.Arg925Ter stop_gained De novo - - 28135719 et al. (2017)
c.2448C>A p.Tyr816Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1480A>T p.Lys494Ter stop_gained De novo - - 27148574 Yang H , et al. (2016)
c.784C>T p.Gln262Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
- - translocation De novo - Simplex 25574029 Quintero-Rivera F , et al. (2015)
c.3814C>T p.Arg1272Ter stop_gained De novo - - 29158550 Popp B , et al. (2017)
c.1706C>T p.Ala569Val stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2062C>T p.Arg688Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2644C>T p.Gln882Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2706C>G p.Ser902Arg stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2908C>T p.Gln970Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.979C>T p.Gln327Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.3989C>A p.Ser1330Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.1759C>T p.Arg587Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.2188G>T p.Glu730Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.2473C>T p.Gln825Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.2932C>T p.Gln978Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.692C>T p.Pro231Leu stop_gained De novo - - 30152016 Ritter AL , et al. (2018)
c.3204C>G p.Tyr1068Ter stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.3446C>T p.Thr1149Ile stop_gained De novo - - 33644933 Khayat MM et al. (2021)
c.2473C>T p.Gln825Ter stop_gained De novo - - 30152016 Ritter AL , et al. (2018)
c.979C>T p.Gln327Ter stop_gained Unknown - - 30622101 Murdock DR , et al. (2019)
c.1231G>A p.Gly411Ser missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1819G>A p.Asp607Asn missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2002C>T p.Arg668Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2495G>A p.Arg832His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2866C>T p.Arg956Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1639C>T p.Arg547Cys missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.3814C>T p.Arg1272Ter stop_gained De novo - - 38177409 M Cecilia Poli et al. ()
c.3331C>T p.Arg1111Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3805C>T p.Arg1269Trp missense_variant De novo - - 33004838 Wang T et al. (2020)
c.3233C>T p.Ala1078Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3849G>A p.Lys1283= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4431G>A p.Pro1477= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.139C>T p.Pro47Ser missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.3623G>A p.Trp1208Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.1459C>T p.Arg487Trp missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.1610G>A p.Gly537Asp missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.1642G>A p.Gly548Ser missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.1646G>A p.Arg549His missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.1819G>A p.Asp607Asn missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.2374G>C p.Gly792Arg missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.2520del p.Arg841AlafsTer91 frameshift_variant De novo - - 28135719 et al. (2017)
c.2188G>T p.Glu730Ter stop_gained De novo - Simplex 35716097 Romano F et al. (2022)
c.4042T>C p.Ser1348Pro missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.4370A>G p.Asp1457Gly missense_variant De novo - - 34950897 Khayat MM et al. (2021)
c.4432C>T p.Pro1478Ser missense_variant Unknown - - 34950897 Khayat MM et al. (2021)
c.2526G>A p.Ser842= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.994C>T p.Gln332Ter stop_gained De novo - Simplex 35597848 Carvalho LML et al. (2022)
c.2188del p.Glu730ArgfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1788_1789del p.Gln598AlafsTer44 frameshift_variant De novo - - 28135719 et al. (2017)
c.2248_2249del p.Leu750ValfsTer17 frameshift_variant De novo - - 28135719 et al. (2017)
c.1122dup p.Gly375ArgfsTer3 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.877G>T p.Glu293Ter stop_gained Unknown Not maternal - 36980980 Spataro N et al. (2023)
c.4000G>A p.Gly1334Ser missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.4711C>T p.Pro1571Ser missense_variant Familial - - 39654053 Paola Granata et al. (2024)
c.648C>T p.Pro216= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4288dup p.Gln1430ProfsTer51 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1945del p.Ala649ProfsTer83 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.1348del p.Glu450SerfsTer2 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.2062C>T p.Arg688Ter stop_gained De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.2649G>A p.Arg883= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.677_680dup p.Glu228ProfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1881del p.Gln627HisfsTer105 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.3809del p.Gln1270ArgfsTer75 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.1162del p.Asp388IlefsTer64 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.1453del p.Leu485TrpfsTer14 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.1624del p.Ile542PhefsTer43 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.643dup p.Ser215LysfsTer16 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.1122dup p.Gly375ArgfsTer3 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.1122dup p.Gly375ArgfsTer3 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.1541C>T p.Ser514Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4065C>T p.Ser1355= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4289dup p.Ala1432GlyfsTer49 frameshift_variant De novo - - 35716097 Romano F et al. (2022)
c.1446del p.Val483TyrfsTer16 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.2849del p.Pro950ArgfsTer192 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.4438del p.Glu1480LysfsTer67 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.1818dup p.Asp607ArgfsTer36 frameshift_variant De novo - - 30152016 Ritter AL , et al. (2018)
c.244G>A p.Asp82Asn missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3427dup p.Leu1143ProfsTer23 frameshift_variant De novo - - 30152016 Ritter AL , et al. (2018)
c.807del p.Glu270SerfsTer19 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3265_3270dup p.Ser1090_Ser1091dup inframe_insertion De novo - - 35982159 Zhou X et al. (2022)
c.2373_2374del p.Cys791TrpfsTer57 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.2529_2545del p.Asp845ArgfsTer40 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.2229del p.Ser744ProfsTer188 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.1122del p.Pro376LeufsTer76 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1402dup p.Cys468LeufsTer49 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3019_3020insAGCCT p.Ser1007LysfsTer137 frameshift_variant De novo - - 28135719 et al. (2017)
c.2547del p.Ser850ProfsTer82 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.1306_1307del p.Pro436ThrfsTer80 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.3313del p.Ala1105LeufsTer37 frameshift_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.2898del p.Tyr967ThrfsTer175 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.1206del p.Arg403AlafsTer49 frameshift_variant De novo - Simplex 35596688 Danda S et al. (2022)
c.1758del p.Lys586AsnfsTer37 frameshift_variant De novo - Simplex 35596688 Danda S et al. (2022)
c.2373_2374del p.Cys791TrpfsTer57 frameshift_variant De novo - - 33644933 Khayat MM et al. (2021)
c.1446del p.Val483TyrfsTer16 frameshift_variant De novo - Simplex 35716097 Romano F et al. (2022)
c.2192dup p.Asp732ArgfsTer36 frameshift_variant De novo - Multiplex 35716097 Romano F et al. (2022)
c.1758dup p.Arg587ThrfsTer56 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2373_2374del p.Cys791TrpfsTer57 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.514dup p.Ser172LysfsTer8 frameshift_variant De novo - Simplex 34073322 Della Vecchia S et al. (2021)
c.1102_1114del p.Cys368AlafsTer80 frameshift_variant De novo - Multiplex 35716097 Romano F et al. (2022)
c.1181_1182del p.Cys394SerfsTer122 frameshift_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.1481_1482del p.Lys494SerfsTer22 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1937_1938delTG p.Val646AlafsTer frameshift_variant Unknown - Simplex 40046197 Burcu KardaÅŸ et al. (2025)
c.1814_1819delinsT p.Ala605ValfsTer36 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

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."

4/1/2021
1
icon
1

Score remained at 1

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria. An additional 14 previously unreported individuals with de novo truncating mutations in the AHDC1 gene were presented in Jiang et al., 2018; three of these novel cases were reported to have had a prior diagnosis of autism or ASD.

Reports Added
[Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome2021] [Focusing on Autism Spectrum Disorder in Xia-Gibbs Syndrome: Description of a Female with High Functioning Autism and Literature Review2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria. An additional 14 previously unreported individuals with de novo truncating mutations in the AHDC1 gene were presented in Jiang et al., 2018; three of these novel cases were reported to have had a prior diagnosis of autism or ASD.

Reports Added
[Prevalence and architecture of de novo mutations in developmental disorders2017] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria. An additional 14 previously unreported individuals with de novo truncating mutations in the AHDC1 gene were presented in Jiang et al., 2018; three of these novel cases were reported to have had a prior diagnosis of autism or ASD.

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

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria. An additional 14 previously unreported individuals with de novo truncating mutations in the AHDC1 gene were presented in Jiang et al., 2018; three of these novel cases were reported to have had a prior diagnosis of autism or ASD.

Reports Added
[Xia-Gibbs Syndrome in adulthood: a case report with insight into the natural history of the condition.2019]
10/1/2018
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria. An additional 14 previously unreported individuals with de novo truncating mutations in the AHDC1 gene were presented in Jiang et al., 2018; three of these novel cases were reported to have had a prior diagnosis of autism or ASD.

Reports Added
[Variable Clinical Manifestations of Xia-Gibbs syndrome: Findings of Consecutively Identified Cases at a Single Children's Hospital.2018]
10/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Reports Added
[Exome Pool-Seq in neurodevelopmental disorders.2017]
4/1/2017
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disabili...2016] [De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.2014] [MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Reports Added
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
3S
icon
3S

Decreased from 3S to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
icon
3S

Increased from to 3S

Description

Mutations in the AHDC1 gene were found in four individuals presenting with a syndrome characterized by intellectual disability, expressive language delay, hypotonia, and obstructive sleep apnea, which was subsequently classified as Xia-Gibbs syndrome (OMIM 615829), (Xia et al., 2014). One of the original subjects from the Xia et al., 2014 study (subject 4) is described as having "noncommunicating autism" as a clinical feature in Table 1. Novel de novo variants in the AHDC1 gene (one frameshift, one missense variant predicted to be benign) were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Exome sequencing of 2157 cases with intellectual disability or developmental delay in Yang et al., 2016 identified seven proband-patient trios with de novo AHDC1 variants; probands typically presented with developmental delay, intellectual disability, absent or limited speech, hypotonia, dysmorphic features, brain abnormalities, failure to thrive/feeding difficulties, and ataxia/gait abnormalities, and two of the seven probands were additionally diagnosed with autism based on DSM-IV or DSM-V criteria.

Krishnan Probability Score

Score 0.48935682110503

Ranking 6504/25841 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 0.99943144781763

Ranking 960/18225 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
Iossifov Probability Score

Score 0.975

Ranking 50/239 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
Original Source
Sanders TADA Score

Score 0.46465407393228

Ranking 378/18665 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 0.26241890795117

Ranking 3300/20870 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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