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

TY - JOUR

T1 - Low-pass whole-genome sequencing in clinical cytogenetics

T2 - a validated approach

AU - Dong, Zirui

AU - Zhang, Jun

AU - Hu, Ping

AU - Chen, Haixiao

AU - Xu, Jinjin

AU - Tian, Qi

AU - Meng, Lu

AU - Ye, Yanchou

AU - Wang, Jun

AU - Zhang, Meiyan

AU - Li, Yun

AU - Wang, Huilin

AU - Yu, Shanshan

AU - Chen, Fang

AU - Xie, Jiansheng

AU - Jiang, Hui

AU - Wang, Wei

AU - Choy, Kwong Wai

AU - Xu, Zhengfeng

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - molecular karyotyping

KW - next-generation sequencing

KW - pathogenic copy-number variants

U2 - 10.1038/gim.2015.199

DO - 10.1038/gim.2015.199

M3 - Journal article

C2 - 26820068

SN - 1098-3600

VL - 18

SP - 940

EP - 948

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 9

ER -