Whole-exome sequencing analysis to identify novel potential pathogenetic mutations in fetuses with abnormal brain structure

BACKGROUND: Genetic mutations in genes related to the production, migration, or differentiation of cortical neurons can result in malformations of cortical development (MCDs). However, a large number of MCD-related pathogenetic mutations remain unknown. This study aimed to investigate the genetic cause of MCDs and to identify the new MCD-associated mutations through whole‐exome sequencing (WES) in fetuses with abnormal brain structure. METHODS: Cord venous blood samples were collected from 11 fetuses with MCDs. Whole-genome DNA was extracted from the blood, and WES was performed. Single nucleotide substitutions, insertions, and deletions were detected by bioinformatics analysis. Genetic mutations in genes associated with MCD were identified. RESULTS: A total of 1035 genes with high-impact genetic variants in at least 1 fetus were identified. The results of gene ontology enrichment analysis were consistent with those of previous studies and also indicated new potential MCD-related pathogenetic genetic mutations. Genes with high-impact mutations in multiple fetuses, such as CTDSP2 and C-terminal binding protein 2 (CTBP2), were more likely to be the genes affecting normal brain development. CONCLUSIONS: This study has characterized variations in fetuses with MCDs and identified potential genetic mutations causing MCDs. Our findings extend the mutation spectrum of MCDs and provide a promising source for the identification of MCD-related pathogenetic mutations.