HGNC Approved Gene Symbol: AHDC1
SNOMEDCT: 774068004;
Cytogenetic location: 1p36.11-p35.3 Genomic coordinates (GRCh38) : 1:27,534,245-27,604,227 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11-p35.3 | Xia-Gibbs syndrome | 615829 | Autosomal dominant | 3 |
Xia et al. (2014) reported that the deduced 1,603-amino acid AHDC1 protein has evolutionarily conserved regions in its N- and C-terminal halves. The conserved domain in its N-terminal half includes 2 AT-hook DNA-binding motifs. Orthologs of AHDC1 were found only in vertebrates.
Xia et al. (2014) determined that the AHDC1 gene contains 5 noncoding 5-prime exons, a single 4.9-kb coding exon, and a noncoding 3-prime exon.
By genomic sequence analysis, Xia et al. (2014) mapped the AHDC1 gene to chromosome 1p36.11.
In a girl with Xia-Gibbs syndrome (XIGIS; 615829), Xia et al. (2014) identified a de novo heterozygous truncating mutation in the AHDC1 gene (615790.0001). The mutation was found by whole-exome sequencing. Targeted sequencing of the AHDC1 gene in 2,000 additional patients identified 3 patients with a similar disorder who had de novo heterozygous truncating mutations (615790.0002-615790.0003). Functional studies of the variants were not performed.
In 7 unrelated individuals with XIGIS, Yang et al. (2015) identified de novo truncating mutations in exon 6 of the AHDC1 gene. The mutations were identified after whole-exome sequencing in 2,157 patients with intellectual disability or developmental delay; they were confirmed by Sanger sequencing. Six of the mutations were novel and 1 (615790.0001) was previously reported. Functional studies were not performed.
Garcia-Acero and Acosta (2017) identified a de novo heterozygous mutation in the AHDC1 gene (615790.0004) in an 8-year-old Colombian girl with XIGIS. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
Ritter et al. (2018) reported 4 additional patients with XIGIS and novel de novo truncating mutations in exon 6 of the AHDC1 gene. The mutations were identified by whole-exome sequencing. Functional studies were not performed.
In an 18-month-old girl of European descent with mental retardation, failure to thrive, hypotonia, absent expressive language, obstructive sleep apnea, and mild dysmorphic features (XIGIS; 615829), Xia et al. (2014) identified a de novo heterozygous 2-bp deletion (c.2373_2374delTG) in the AHDC1 gene, resulting in a frameshift and premature termination (Cys791TrpfsTer57). The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases, or in 8,000 in-house controls. The same de novo mutation was subsequently found in an 8-year-old boy of European descent with a similar disorder. Functional studies of the variant were not performed.
In a 5-year-old boy with Xia-Gibbs syndrome, Yang et al. (2015) identified the de novo heterozygous c.2373_2374delTG mutation in the AHDC1 gene. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to cause a truncation downstream of the AT-hook motif and to eliminate the PDZ-binding domain consensus sequence. The patient had developmental delay, hypotonia, dysmorphisms, ataxia, joint laxity, and seizures.
In a 4-year-old girl of south Asian descent with Xia-Gibbs syndrome (XIGIS; 615829), Xia et al. (2014) identified a de novo heterozygous 1-bp deletion (c.2898delC) in the AHDC1 gene, resulting in a frameshift and premature termination (Tyr967ThrfsTer175). Functional studies of the variant were not performed.
In an 11-year-old boy of European descent with Xia-Gibbs syndrome (XIGIS; 615829), Xia et al. (2014) identified a de novo heterozygous 1-bp deletion (c.2547delC) in the AHDC1 gene, resulting in a frameshift and premature termination (Ser850ProfsTer82). Functional studies of the variant were not performed.
In an 8-year-old Colombian girl with Xia-Gibbs syndrome (XIGIS; 615829), Garcia-Acero and Acosta (2017) identified a de novo 1-bp deletion (c.2030delG) in a conserved region of the AHDC1 gene, resulting in a frameshift and premature termination (Gly677AlafsTer55). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. No truncating mutations in the AHDC1 gene were found in the dbSNP and ExAC databases. Functional studies were not performed.
In a 2-year-old Turkish girl with Xia-Gibbs syndrome (XIGIS; 615829), Gumus (2020) identified a de novo c.4370A-G transition (c.4370A-G, NM_001029882) in exon 6 of the AHDC1 gene, resulting in an asp1457-to-gly (D1457G) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was absent in the ExAC, 1000 Genomes Project, and NHLBI Exome Sequencing Project databases. Functional studies were not performed. The patient had developmental delay, structural brain abnormalities, seizures, and craniosynostosis.
Garcia-Acero, M., Acosta, J. Whole-exome sequencing identifies a de novo AHDC1 mutation in a Colombian patient with Xia-Gibbs syndrome. Molec. Syndromol. 8: 308-312, 2017. [PubMed: 29230160] [Full Text: https://doi.org/10.1159/000479357]
Gumus, E. Extending the phenotype of Xia-Gibbs syndrome in a two-year-old patient with craniosynostosis with a novel de novo AHDC1 missense mutation. Europ. J. Med. Genet. 63: 103637, 2020. [PubMed: 30858058] [Full Text: https://doi.org/10.1016/j.ejmg.2019.03.001]
Ritter, A. L., McDougall, C., Skraban, C., Medne, L., Bedoukian, E. C., Asher, S. B., Balciuniene, J., Campbell, C. D., Baker, S. W., Denenberg, E. H., Mazzola, S., Fiordaliso, S. K., Krantz, I. D., Kaplan, P., Ierardi-Curto, L., Santani, A. B., Zackai, E. H., Izumi, K. Variable clinical manifestations of Xia-Gibbs syndrome: findings of consecutively identified cases at a single children's hospital. Am. J. Med. Genet. 176A: 1890-1896, 2018. [PubMed: 30152016] [Full Text: https://doi.org/10.1002/ajmg.a.40380]
Xia, F., Bainbridge, M. N., Tan, T. Y., Wangler, M. F., Scheuerle, A. E., Zackai, E. H., Harr, M. H., Sutton, V. R., Nalam, R. L., Zhu, W., Nash, M., Ryan, M. M., and 12 others. De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet. 94: 784-789, 2014. [PubMed: 24791903] [Full Text: https://doi.org/10.1016/j.ajhg.2014.04.006]
Yang, H., Douglas, G., Monaghan, K. G., Retterer, K., Cho, M. T., Escobar, L. F., Tucker, M. E., Stoler, J., Rodan, L. H., Stein, D., Marks, W., Enns, G. M., and 9 others. 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. Cold Spring Harbor Molec. Case Stud. 1: a000562, 2015. Note: Electronic Article. [PubMed: 27148574] [Full Text: https://doi.org/10.1101/mcs.a000562]