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

Abstract

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

Keywords: central hypotonia; intellectual disability, severe; severe global developmental delay.

Figure 1.

Facial characteristics of individuals with AHDC1 variants including a high, broad prominent forehead, hypertelorism, depressed nasal bridge, and thin upper lip.

Figure 2.

AHDC1 gene organization and distribution of truncating mutations. AHDC1 consists of seven exons with only one coding (exon 6). Three mutations above the schematic protein were reported by Xia et al. (2014). Six mutations below the schematic protein are novel mutations reported in this study. The mutation in the box reported by Xia et al. was found in one of our probands.