Human Gene Module / Chromosome 1 / AHDC1

AHDC1AT-hook DNA binding motif containing 1

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 10
Rare Variants / Common Variants
37 / 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 CardEntrez GeneOMIMUniProtHumanBasePubMed
Reports related to AHDC1 (10 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 Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
8 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No Behavioral anomalies, microcephaly
9 Recent Recommendation The phenotypic spectrum of Xia-Gibbs syndrome. Jiang Y , et al. (2018) No ASD
10 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
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2373_2374delTG p.Cys791TrpfsTer57 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.2898delC p.Tyr967ThrfsTer175 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.2373_2374delTG p.Cys791TrpfsTer57 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
c.2547delC p.Ser850ProfsTer82 frameshift_variant De novo - Simplex 24791903 Xia F , et al. (2014)
1760+A R587+! frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1541C>T p.Ser514Leu missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
- - translocation De novo - Simplex 25574029 Quintero-Rivera F , et al. (2015)
c.1945delG p.Ala649ProfsTer83 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.2529_2545del17 p.Asp845ArgfsTer40 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.1881delG p.Gln627HisfsTer105 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.1122dupC p.Gly375ArgfsTer3 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.3809delA p.Gln1270ArgfsTer75 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.2373_2374delTG p.Cys791TrpfsTer57 frameshift_variant De novo - - 27148574 Yang H , et al. (2016)
c.1480A>T p.Lys494Ter stop_gained De novo - - 27148574 Yang H , et al. (2016)
c.1402dup p.Cys468fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.2229delG - frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.3814C>T p.Arg1272Ter stop_gained De novo - - 29158550 Popp B , et al. (2017)
c.2644C>T p.Gln882Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2520delT p.Arg841AlafsTer91 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.2229delG p.Ser744ProfsTer188 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.2773C>T p.Arg925Ter 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.2908C>T p.Gln970Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2691delA p.Val898TrpfsTer34 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.2908C>T p.Gln970Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.784C>T p.Gln262Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.3989C>A c.Ser1330Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2415delG p.Leu806TrpfsTer126 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.2773C>T p.Arg925Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2373_2374delTG p.Cys791TrpfsTer57 frameshift_variant De novo - - 29696776 Jiang Y , et al. (2018)
c.3773C>G p.Ser1258Ter stop_gained De novo - - 29696776 Jiang Y , et al. (2018)
c.2473C>T p.Gln825Ter stop_gained De novo - - 30152016 Ritter AL , et al. (2018)
c.4494dupG p.Cys1499ValfsTer9 frameshift_variant De novo - - 30152016 Ritter AL , et al. (2018)
c.2885dupC p.Pro963fs frameshift_variant De novo - - 30152016 Ritter AL , et al. (2018)
c.1759C>T p.Arg587Ter stop_gained De novo - - 30152016 Ritter AL , et al. (2018)
- - copy_number_loss Unknown - - 30152016 Ritter AL , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

3S

Score Delta: Score remained at 3.3 + S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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."

4/1/2018
3S
icon
3.3 + S

Score remained at 3.3 + S

Description

3S

Reports Added
[The phenotypic spectrum of Xia-Gibbs syndrome.2018]
4/1/2017
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.

Reports Added
[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] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disabili...2016]
10/1/2016
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.

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

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016]
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
CNVs associated with AHDC1(1 CNVs)
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1p36.11-p35.3 3 Deletion 5  /  3
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