ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 1p36.11-p35.3
  • GRCh37/hg19 chr1: 27,860,756-27,930,143
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr1: 27,534,245-27,604,178
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24791903 Xia et al. (2014) reported four patients (subject 1-4) with de novo frameshift mutations resulting in a premature termination codon of the AHDC1 gene. The overlapping phenotype for the all patients included intellectual disability, global developmental delay, speech delay, hypotonia, anatomic upper-airway obstruction, brain MRI demonstrating hypoplasia of the corpus callosum and gyral simplification, and mildly dysmorphic facial features (i.e. protuberant low-set ears, flat nasal bridge, hypertelorism, micrognathia and esotropia). The reported mutations are listed as follows: subject 1 has a 2-bp deletion [c.2373_2374delTG (p.Cys791Trpfs*57)], subject 2 has a 1-bp deletion [c.2898delC (p.Tyr967Thrfs*175)], subject 3 has a 2-bp deletion [c.2373_2374delTG (p.Cys791Trpfs*57)] and subject 4 has a 1-bp deletion [c.2547delC (p.Ser850Profs*82)]. These mutations may truncate the conserved region 2 of the AHDC1 gene, whilst preserving the conserved region 1. As the mutation occurs in a single coding exon 6, the modified mRNA may escape nonsense-mediated decay. Hence, the author suggested that the autosomal dominant mode of inheritance for these mutations may be due to the formation of dominant-negative proteins. No functional studies were performed in this study (See PMID: 25574029 below for expression studies).
27148574 Yang et al. (2015) reported seven patients with a de novo mutation (six frameshift and one substitution) resulting in premature termination codon of the AHDC1 gene. The overlapping phenotype for all patients included intellectual disabilities, global developmental delay, nonverbal or limited ability for verbal expressive language, problems with muscle tone, ataxia, behavioral issues, problems with sleep (i.e. apnea), brain MRI showed thin corpus callosum, dysmorphic facial features (i.e. short nose, brachycephaly, plagiocephaly and highly arched palate) and other medical features (i.e. problems with growth, epilepsy, nystagmus, omphalocele and club foot). The reported mutations are: patient 1 has a 1-bp deletion [c.1945delG (p.Ala649Profs*83)], patient 2 has a 17-bp deletion [c2529_2545del17 (p.Asp845Argfs*40)], patient 3 has a 1-bp deletion [c.1881delG (p.Ala627Hisfs*105)], patient 4 has a 1-bp duplication [c.1122dupC (p.Gly375Argfs*3)], patient 5 has a 1-bp deletion [c.3809delA (p.Gln1270Argfs*75)], patient 6 has a 2-bp deletion [c2373_2374delTG (p.Cys791Trpfs*57)] and patient 7 has a substitution mutation [c.1480 A>T (p.Lys494Ter)]. As the truncation occurs in the single coding exon 6 of the AHDC1 gene, nonsense-mediated mRNA decay is unlikely. Five of these mutations (Patient 1, 2, 3, 5 and 6) are predicted to cause protein truncation beyond the AT-hook motifs and eliminate the PDZ binding domain consensus sequence. The remaining two mutations (Patient 4 and 7) lead to an even earlier stop of translation, where both conserved regions 1 and 2 are disrupted. Missing the functional domains that interact with other proteins (i.e. PDZ domain proteins) may compromise the regulation of multiple biological processes that could be important for brain development and function. No functional studies were performed.
29230160 Garcia-Acero and Acosta (2017) reported one patient with a de novo 1-bp deletion causing a frameshift of the AHDC1 gene open reading frame resulting in a premature termination codon after 52 amino acids [c.2030_2030delG (p.Gly677Alafs*52)]. This patient required mechanical ventilation at birth for 27 days. The clinical follow-up showed hypotonia, developmental and speech delay, and dysmorphic facial features (i.e. midfacial hypoplasia, hypertelorism, micrognathia, epicanthic fold, upslanting palpebral fissures). The brain MRI revealed frontal and temporal cortical atrophy with loss of posterior ventricular white matter.

Haploinsufficiency phenotype comments:

There are other reported cases with de novo truncating mutations within the single exon 6 leading to a premature termination codon that consequently resulting in loss-of-function of the AHDC1 gene. They are: patient S_078 [c.3814C>T (p.Arg1272*)] (PMID: 29158550), patient 24 [c.2373_2374delTG (p.Cys791Trpfs*57)] (PMID: 27884935) and patient 7 [c.1402dup (p.Cys468Leufs*49)] (PMID: 26350515). According to cases submitted on ClinVar, there is no evidence of missense mutations of AHDC1 gene being clinically significant. Furthermore, Quintero-Rivera et al. (2015) described one case (PMID: 25574029) of a de novo balanced translocation [46,XY,t(1;5)(p36.11;q31.2)dn] was reported with the breakpoint on the derivative chromosome 1 was at intron 1 (5'UTR is intact) of the AHDC1 gene. At this breakpoint, it was also found to have a 13-bp deletion. Hence, exon 2-7 of the AHDC1 gene were relocated to the derivative chromosome 5. Phenotype shared in common with other reported cases included impaired intellectual, speech and motor development. This patient also has facial dysmorphism, and respiratory and sleep disturbances. Interestingly, the AHDC1 gene expression study showed ~50% reduction in this patient lymphoblastoid cells suggesting haploinsufficiency is the reason for the phenotype. In mice, Ahdc1 is expressed at embryonic day E11.5 and E16.5 in the developing brain, supporting the AHDC1 gene involvement in brain development. In addition, one recent case report by Park et al. (2017) (PMID: 28841002) describing a ~1 Mb deletion from chromosome region 1p36.11 to 1p35.3 (chr1:27750155-28754771). The deletion involved thirteen OMIM genes including the AHDC1 gene. Interestingly, the clinical features of this patient included hypotonia, delay in receptive language cognitive ability, delay in fine and gross motor skills, and brain MRI showed corpus of callosum thinning. As such, the author suggested that the patient's phenotype more closely resembled that of cases with de novo truncated mutations in AHDC1 gene.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity