Human Gene Module / Chromosome 1 / AHDC1

AHDC1AT-hook DNA binding motif containing 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
54 / 0
Aliases
AHDC1, MRD25
Associated Syndromes
Xia-Gibbs syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
1p36.11-p35.3
Associated Disorders
ASD
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 GeneOMIMUniProtHumanBase
Reports related to AHDC1 (13 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 disabili... 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 -
Rare Variants   (54)
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 NA - 28135719 et al. (2017)
c.2188G>T p.Glu730Ter stop_gained De novo NA - 28135719 et al. (2017)
c.2773C>T p.Arg925Ter stop_gained De novo NA - 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 NA - 27148574 Yang H , et al. (2016)
c.784C>T p.Gln262Ter stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
- - translocation De novo NA Simplex 25574029 Quintero-Rivera F , et al. (2015)
c.3814C>T p.Arg1272Ter stop_gained De novo NA - 29158550 Popp B , et al. (2017)
c.1706C>T p.Ala569Val stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.2062C>T p.Arg688Ter stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.2644C>T p.Gln882Ter stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.2706C>G p.Ser902Arg stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.2908C>T p.Gln970Ter stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.979C>T p.Gln327Ter stop_gained Unknown - - 30622101 Murdock DR , et al. (2019)
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.3989C>A p.Ser1330Ter stop_gained De novo NA - 29696776 Jiang Y , et al. (2018)
c.692C>T p.Pro231Leu stop_gained De novo NA - 30152016 Ritter AL , et al. (2018)
c.3331C>T p.Arg1111Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2473C>T p.Gln825Ter stop_gained De novo NA - 30152016 Ritter AL , et al. (2018)
c.1231G>A p.Gly411Ser missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1819G>A p.Asp607Asn missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.3805C>T p.Arg1269Trp missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.2520del p.Arg841AlafsTer91 frameshift_variant De novo NA - 28135719 et al. (2017)
c.2188del p.Glu730ArgfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1788_1789del p.Gln598AlafsTer44 frameshift_variant De novo NA - 28135719 et al. (2017)
c.2248_2249del p.Leu750ValfsTer17 frameshift_variant De novo NA - 28135719 et al. (2017)
c.677_680dup p.Glu228ProfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1122dup p.Gly375ArgfsTer3 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.4288dup p.Gln1430ProfsTer51 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1945del p.Ala649ProfsTer83 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.1348del p.Glu450SerfsTer2 frameshift_variant De novo NA - 29696776 Jiang Y , et al. (2018)
c.1881del p.Gln627HisfsTer105 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.3809del p.Gln1270ArgfsTer75 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.1162del p.Asp388IlefsTer64 frameshift_variant De novo NA - 29696776 Jiang Y , et al. (2018)
c.1453del p.Leu485TrpfsTer14 frameshift_variant De novo NA - 29696776 Jiang Y , et al. (2018)
c.1624del p.Ile542PhefsTer43 frameshift_variant De novo NA - 29696776 Jiang Y , et al. (2018)
c.1541C>T p.Ser514Leu missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1818dup p.Asp607ArgfsTer36 frameshift_variant De novo NA - 30152016 Ritter AL , et al. (2018)
c.3427dup p.Leu1143ProfsTer23 frameshift_variant De novo NA - 30152016 Ritter AL , et al. (2018)
c.807del p.Glu270SerfsTer19 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.2373_2374del p.Cys791TrpfsTer57 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.2529_2545del p.Asp845ArgfsTer40 frameshift_variant De novo NA - 27148574 Yang H , et al. (2016)
c.2229del p.Ser744ProfsTer188 frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.1122del p.Pro376LeufsTer76 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.1402dup p.Cys468LeufsTer49 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.3019_3020insAGCCT p.Ser1007LysfsTer137 frameshift_variant De novo NA - 28135719 et al. (2017)
c.2547del p.Ser850ProfsTer82 frameshift_variant De novo NA Simplex 24791903 Xia F , et al. (2014)
c.1306_1307del p.Pro436ThrfsTer80 frameshift_variant De novo NA - 29696776 Jiang Y , et al. (2018)
c.2898del p.Tyr967ThrfsTer175 frameshift_variant De novo NA Simplex 24791903 Xia F , et al. (2014)
c.1758dup p.Arg587ThrfsTer56 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.2373_2374del p.Cys791TrpfsTer57 frameshift_variant De novo NA Simplex 24791903 Xia F , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 3S

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.

10/1/2020
3S
icon
3S

Score remained at 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
[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]
4/1/2018
3S
icon
3.3 + S

Decreased from 3S to 3.3 + S

Description

3S

Reports Added
[The phenotypic spectrum of Xia-Gibbs syndrome.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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