Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Rolph Pfundt, Marisol del Rosario, Lisenka E. L. M. Vissers, Michael P. Kwint, Irene M. Janssen, Nicole de Leeuw, Helger G. Yntema, Marcel R. Nelen, Dorien Lugtenberg, Erik-Jan Kamsteeg, Nienke Wieskamp, Alexander P. A. Stegmann, Servi J. C. Stevens, Richard J. T. Rodenburg, Annet Simons, Arjen R. Mensenkamp, Tuula Rinne, Christian Gilissen, Hans Scheffer, Joris A. VeltmanJayne Y. Hehir-Kwa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

101 Citations (Web of Science)

Abstract

Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a firsttier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome-or genome-wide approach with a single test.

Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.

Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of similar to 2%(ranging from 0 to -5.8% per disorder).

Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.

Original languageEnglish
Pages (from-to)667-675
Number of pages9
JournalGenetics in Medicine
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2017

Keywords

  • copy-number variants
  • diagnostic yield
  • exome sequencing
  • read depth
  • structural variation
  • SEVERE INTELLECTUAL DISABILITY
  • CONGENITAL-ANOMALIES
  • STRUCTURAL VARIATION
  • DEVELOPMENTAL DELAY
  • QT SYNDROME
  • GENOME
  • MODEL
  • MAP
  • POLYMORPHISM
  • INSERTIONS

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