AHDC1 missense mutations in Xia-Gibbs syndrome

Abstract

Summary 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.

Long read sequencing and expression studies ofAHDC1deletions in Xia‐Gibbs syndrome reveal a novel genetic regulatory mechanism

“…Phenotypes are categorized into high‐level categories: comprehensive skills and language, musculoskeletal, neurologic, head and neck, vision and hearing, and other features. XGS core features are marked with † and derived from Figure 2 (Khayat, Hu, et al, 2021).…”

“…Most individuals clinically diagnosed with XGS harbor de novo protein‐truncating mutations predicted to lead to truncated versions of the AHDC1 protein (Jiang et al, 2018; Khayat, Li, et al, 2021). In addition to the individuals with de novo protein‐truncating mutations, at least 10 individuals have been reported as diagnosed with XGS based upon the presence of de novo missense mutations in AHDC1 (Gumus, 2020; Khayat, Hu, et al, 2021). Mapping these missense mutations to the protein sequence identifies at least two sensitive domains that overlap with regions of predicted functional motifs (Khayat, Hu, et al, 2021).…”

“…In addition to the individuals with de novo protein‐truncating mutations, at least 10 individuals have been reported as diagnosed with XGS based upon the presence of de novo missense mutations in AHDC1 (Gumus, 2020; Khayat, Hu, et al, 2021). Mapping these missense mutations to the protein sequence identifies at least two sensitive domains that overlap with regions of predicted functional motifs (Khayat, Hu, et al, 2021). The reported 10 pathogenic missense variants that result in XGS are predicted to result in full‐length protein products and are also likely to act via a dominant‐negative or other GoF mechanism (Khayat, Hu, et al, 2021).…”

“…Mapping these missense mutations to the protein sequence identifies at least two sensitive domains that overlap with regions of predicted functional motifs (Khayat, Hu, et al, 2021). The reported 10 pathogenic missense variants that result in XGS are predicted to result in full‐length protein products and are also likely to act via a dominant‐negative or other GoF mechanism (Khayat, Hu, et al, 2021).…”

First reported cases with Xia‐Gibbs syndrome from India harboring novel variants in AHDC1

“…The majority of the mutations in AHDC1 causing XGS are truncating. However, recently de novo missense mutations involving probable functional domains in the conserved regions of AHDC1 have also been reported (Khayat et al, 2021). Clinical heterogeneity of this syndrome makes diagnosis difficult without molecular testing, hence next generation sequencing becomes mandatory for accurate diagnosis, management and genetic counseling (Jiang et al, 2018).…”