AHDC1 missense mutations in Xia-Gibbs syndrome

Abstract

Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.

Figure 1

Recorded AHDC1 missense cases and protein sequence mutability (A) A total of 10 individuals with de novo or suspected de novo missense mutations in AHDC1 are shown. (B) The AHDC1 missense mutations are scored using the missense tolerance ratio score. A lower score indicates a higher intolerance to missense mutations based on sequence conservation of population controls from gnomAD.

Figure 2

Comparison of XGS phenotypes Data from 34 individuals with XGS due to truncating AHDC1 mutations were compared with those from 5 individuals with suspected or confirmed de novo missense mutations in AHDC1, who have joined the XGS Registry.

Figure 3

Phenotypic similarity network between individuals with AHDC1 variants and OMIM diseases (A) Clustering of individuals with an AHDC1 missense mutation or truncation mutation with 3,464 diseases reported to OMIM based on phenotype similarity illustrated by orange dots, blue dots, and green dots, respectively. (B) Reclustered OMIM disease nodes with at least one connection and similarity >0.1 to individuals with an AHDC1 missense or truncation mutation.