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

• Published in: Children (Basel) Vol. 10; no. 7; p. 1119
• Main Authors: Andres, Erin M, Earnest, Kathleen Kelsey, Xuan, Hao, Zhong, Cuncong, Rice, Mabel L, Raza, Muhammad Hashim
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28-06-2023; MDPI
• Subjects: Articulation disorders in children; Children; English language; Families & family life; family-based; Genes; Genetics; Genotype & phenotype; Grammar; grammar impairment; Grammar, Comparative and general; Language acquisition; Language disorders; language phenotypes; Linguistics; Longitudinal studies; Native language acquisition; pedigree; Speaking; Specific language impairment; Standard scores; whole-exome sequencing; United Kingdom > UK; United States > US; pedigree; language phenotypes; specific language impairment; grammar impairment; whole-exome sequencing; family-based
• ISSN: 2227-9067; 2227-9067
• DOI: 10.3390/children10071119

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 (
= 74 total) and follow-up Sanger sequencing in additional unrelated probands (
= 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (
= 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 (
,
,
,
,
, and
), and two genes previously reported for overall language ability (
and
). We specifically suggest
, a protocadherin gene, and
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.