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 / 7
Rare Variants / Common Variants
17 / 0
Aliases
AHDC1, MRD25
Associated Syndromes
-
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).

Reports related to AHDC1 (7 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 -
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 (2 cases)
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 -
Rare Variants   (17)
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)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

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.

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.

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."

04-01-2017
3S

Initial score established: 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.

CNVs associated with AHDC1(1 CNVs)
1p36.11-p35.3 2 Deletion 4  /  2
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