Next-generation sequencing identifies novel gene variants and pathways involved in specific language impairment

Abstract

A significant proportion of children suffer from unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. These developmental speech and language disorders are highly heritable and have a substantial impact on society. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. Here, we performed whole exome sequencing of 43 unrelated probands affected by severe forms of specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to try to shed new light on the aetiology of the disorder. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidate genes carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential \"multiple-hit\" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. When we broadened our scope to all rare and novel variants throughout the exomes, we identified several biological themes that were enriched for such variants, most notably microtubule transport and cytoskeletal regulation.