Elsevier

Genetics in Medicine

Volume 18, Issue 9, September 2016, Pages 940-948
Genetics in Medicine

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

https://doi.org/10.1038/gim.2015.199Get rights and content
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Abstract

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.

Keywords

molecular karyotyping
next-generation sequencing
pathogenic copy-number variants

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