Incorporation of exome‐based CNV analysis makes trio‐WES a more powerful tool for clinical diagnosis in neurodevelopmental disorders: A retrospective study

Neurodevelopmental disorders (NDDs) are a genetically heterogeneous group of diseases, affecting 1%–3% of children. Whole‐exome sequencing (WES) has been widely used as a first‐tier tool for identifying genetic causes of rare diseases. Trio‐WES was performed in a cohort of 74 pedigrees with NDDs. Exome‐based copy number variant (CNV) calling was incorporated into the traditional single‐nucleotide variant (SNV) and small insertion/deletion (Indel) analysis pipeline for WES data. An overall positive diagnostic yield of 54.05% (40/74) was obtained in the pipeline of combinational SNV/Indel and CNV analysis, including 35.13% (26/74) from SNV/Indel analysis and 18.92% (14/74) from exome‐based CNV analysis, respectively. In total, SNV/Indel analysis identified 38 variants in 28 different genes, of which 24 variants were novel; exome‐based CNV analysis identified 14 CNVs, including 2 duplications and 12 deletions, which ranged from 440 bp (single exon) to 16.86 Mb (large fragment) in size. In particular, a hemizygous deletion of exon 1 in the SLC16A2 gene was detected. Based on the diagnostic results, two families underwent prenatal diagnosis and had unaffected babies. The incorporation of exome‐based CNV detection into conventional SNV/Indel analysis for a single trio‐WES test significantly improved the diagnostic rate, making WES a more powerful, practical, and cost‐effective tool in the clinical diagnosis of NDDs.