1. Results of next‐generation sequencing gene panel diagnostics including copy‐number variation analysis in 810 patients suspected of heritable thoracic aortic disorders
- Author
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Marlies Kempers, Maarten Groenink, Yvonne Hilhorst-Hofstee, Kak K. Yeung, Ingrid P.C. Krapels, Peter van Rijn, Luisa Marsili, Irma van de Beek, Judith M.A. Verhagen, Johanna M. van Hagen, Leonie A. Menke, Arjan C. Houweling, Eelco Dulfer, Eline Overwater, Els Voorhoeve, Marjan M. Weiss, Petra J.G. Zwijnenburg, Marieke J.H. Baars, J. Peter van Tintelen, Alessandra Maugeri, Annette F. Baas, Cardiovascular Centre (CVC), Clinical Genetics, MUMC+: DA KG Polikliniek (9), RS: FHML non-thematic output, ACS - Heart failure & arrhythmias, Graduate School, Human Genetics, General Paediatrics, ANS - Cellular & Molecular Mechanisms, Surgery, Cardiology, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)
- Subjects
0301 basic medicine ,Male ,endocrine system diseases ,thoracic aortic aneurysm ,Aorta, Thoracic ,thoracic aortic dissection ,TGFBR2 MUTATIONS ,Exon ,Gene duplication ,genetics ,Exome ,Copy-number variation ,Receptor, Notch1 ,Genetics (clinical) ,Research Articles ,GENOTYPE-PHENOTYPE CORRELATIONS ,Cyclic GMP-Dependent Protein Kinase Type I ,Genetics ,ARTERIAL-TORTUOSITY-SYNDROME ,eXome hidden Markov model ,High-Throughput Nucleotide Sequencing ,copy‐number variations ,Middle Aged ,Phenotype ,MARFAN-SYNDROME ,Scavenger Receptors, Class F ,Female ,LOEYS-DIETZ-SYNDROME ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Research Article ,Adult ,DNA Copy Number Variations ,Aortic Diseases ,LOSARTAN THERAPY ,Biology ,DNA sequencing ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,mental disorders ,Humans ,Clinical significance ,Genetic Predisposition to Disease ,Genetic Testing ,SYNDROME TYPE-IV ,Chromosome Aberrations ,Aortic Aneurysm, Thoracic ,CLINICAL-FEATURES ,copy-number variations ,MYLK ,030104 developmental biology ,FBN1 MUTATIONS ,EHLERS-DANLOS-SYNDROME - Abstract
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. Eight hundred ten patients suspected of H‐TAD were analyzed 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 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.
- Published
- 2018
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