期刊
HUMAN MUTATION
卷 42, 期 8, 页码 990-1004出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24222
关键词
clinical utility study; diagnostic yield; exome-based CNV analysis; neurodevelopmental disorders; trio-whole-exome sequencing
资金
- Overseas Training Program for Scientific and Technological Talents of Henan Province [2018060]
- Joint Construction Program for Medical Science and Technology Development of Henan Province [LHGJ20190124]
This study focused on using trio-WES for genetic testing in pedigrees with neurodevelopmental disorders, achieving an overall positive diagnostic yield of 54.05%, with 35.13% from SNV/Indel analysis and 18.92% from exome-based CNV analysis. By incorporating CNV detection into conventional SNV/Indel analysis, the diagnostic rate of NDDs was significantly improved.
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.
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