Results of next‐generation sequencing gene panel diagnostics including copy‐number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

Eline Overwater, Luisa Marsili, Marieke J.H. Baars, Annette F. Baas, Irma van de Beek, Eelco Dulfer, Johanna M. van Hagen, Yvonne Hilhorst‐Hofstee, Marlies Kempers, Ingrid P. Krapels, Leonie A. Menke, Judith M.A. Verhagen, Kak K. Yeung, Petra J.G. Zwijnenburg, Maarten Groenink, Peter van Rijn, Marjan M. Weiss, Els Voorhoeve, J. Peter van Tintelen, Arjan C. Houweling, Alessandra Maugeri

Simultaneous analysis of multiple genes using next generation sequencing (NGS) technology has become widely available. Copy number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD) associated genes. 810 patients suspected of H-TAD were analysed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome Hidden Markov Model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 out of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3 and PRKG1 respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients. This article is protected by copyright. All rights reserved.