Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

Abstract

Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study.