Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach

• Published in: Genetics in medicine Vol. 18; no. 9; pp. 940 - 948
• Main Authors: Dong, Zirui, Zhang, Jun, Hu, Ping, Chen, Haixiao, Xu, Jinjin, Tian, Qi, Meng, Lu, Ye, Yanchou, Wang, Jun, Zhang, Meiyan, Li, Yun, Wang, Huilin, Yu, Shanshan, Chen, Fang, Xie, Jiansheng, Jiang, Hui, Wang, Wei, Choy, Kwong Wai, Xu, Zhengfeng
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2016; Elsevier Limited
• Subjects: 631/208/1405; 631/208/1516; 631/208/514/2254; 692/700/139/1512; Abortion, Spontaneous - genetics; Biomedicine; Chromosome Disorders - diagnosis; Chromosome Disorders - genetics; Chromosome Disorders - pathology; Cytogenetics - methods; DNA Copy Number Variations - genetics; Female; Genome, Human - genetics; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Laboratory Medicine; Male; Microarray Analysis; original-research-article; Prenatal Diagnosis; Stillbirth - genetics; next-generation sequencing; molecular karyotyping; pathogenic copy-number variants
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2015.199

Purpose: Chromosomal microarray analysis is the gold standard for copy-number variant (CNV) detection in prenatal and postnatal diagnosis. We aimed to determine whether next-generation sequencing (NGS) technology could be an alternative method for CNV detection in routine clinical application. Methods: Genome-wide CNV analysis (>50 kb) was performed on a multicenter group of 570 patients using a low-coverage whole-genome sequencing pipeline. These samples were referred for chromosomal analysis; CNVs (i.e., pathogenic CNVs, pCNVs) were classified according to the American College of Medical Genetics and Genomics guidelines. Results: Overall, a total of 198 abortuses, 37 stillbirths, 149 prenatal, and 186 postnatal samples were tested. Our approach yielded results in 549 samples (96.3%). In addition to 119 subjects with aneuploidies, 103 pCNVs (74 losses and 29 gains) were identified in 82 samples, giving diagnostic yields of 53.2% (95% confidence interval: 45.8, 60.5), 14.7% (5.0, 31.1), 28.5% (21.1, 36.6), and 30.1% (23.6, 37.3) in each group, respectively. Mosaicism was observed at a level as low as 25%. Conclusions: Patients with chromosomal diseases or microdeletion/microduplication syndromes were diagnosed using a high-resolution genome-wide method. Our study revealed the potential of NGS to facilitate genetic diagnoses that were not evident in the prenatal and postnatal groups. Genet Med 18 9, 940–948.