Identification and Functional Characterization of Variant in the Gene Causing Intellectual Disability

Intellectual disability (ID) is defined by cognitive and social adaptation defects. Variants in the gene, which encodes the brain-specific cytoplasmic protein SYNGAP1, are commonly associated with ID. The aim of this study was to identify novel gene variants in Chinese individuals with ID and evaluate the pathogenicity of the detected variants. Whole exome sequencing (WES) was performed on 113 patients diagnosed with ID. In the study, two variants in were identified. Sanger sequencing was used to confirm these variants. Minigene assays were used to verify whether the intronic variant in influenced the normal splicing of mRNA. Two heterozygous pathogenic variants in c.333del and c.664-2A>G, were identified in two ID patients separately. The c.333del variant has been reported previously as a finding in a child with ID, while the c.664-2A>G variant was novel intronic variant, which has not been reported in the literature. Functional studies showed that c.664-2A>G could cause aberrant splicing, resulting in exon 7 skipping and a 16bp deletion within exon 7. We identified two pathogenic heterozygous variants in in two patients with ID, among which the c.664-2A>G variant was a novel pathogenic variant. Our findings further enrich the variant spectrum of the gene and provide a research basis for the genetic diagnosis of ID.