Novel and recurrent variants identified in fetuses with central nervous system abnormalities by trios-medical exome sequencing

Abstract Background Fetal central nervous system abnormalities often associated with infant death or severe disability. The etiology in fetuses with CNS abnormalities who have normal karyotypes and copy number variants (CNVs) remains unclear, which increases the difficulty in following management and the assessment of prognosis. Method 11 unrelated fetuses with CNS abnormalities and their parents were enrolled. Genomic DNA was obtained and then trios-medical exome sequencing (trios-MES) including 4000 genes (fetuses and their parents) was performed after both karyotyping and chromosome microarray showed negative results. Results Pathogenic and likely pathogenic variants were identified in five of 11 cases (5/11, 45.5%), including five novel mutations and two recurrent mutations in ISPD, L1CAM, and GRIN2B genes. Most cases (4/5, 80%) carried one or two recessive mutations, indicating a high recurrent risk. Conclusion Exome sequencing should be considered for fetuses with CNS abnormalities following negative results of karyotyping and chromosome array. Trios-MES as one of exome sequencing is a potential method for the diagnosis of these fetuses.