Abstract 16049: Diagnostic Yield of Three Years Next Generation Sequencing in Clinical Genetic Diagnostics of Cardiomyopathies
Introduction: The strength of next generation sequencing (NGS) in both research and diagnostics is becoming increasingly evident. NGS is successfully applied to find causal mutations and thus confirm the clinical diagnosis in patients suspected of genetic cardiomyopathies.
Methods: In 2012 NGS analysis was introduced in the diagnostic clinical genetic laboratory in the University Medical Center Groningen. Since then, we analyzed 1153 patients with several types of cardiomyopathies, as specified by the ordering physicians. We used an enrichment kit targeting 55 genes associated with hereditary cardiomyopathies. Two classification trees were used, taking into account population frequencies, in silico predictions, type and location of mutation, conservation scores, clinical data and information from the literature. Additional haplotype and cosegregation analyses were performed to further support pathogenicity of novel potentially causal mutations that had been identified multiple times.
Results: Our approach identified a pathogenic mutation in 14% (157/1153) of patients, thereby explaining the clinical phenotype. In 10% (114/1153) one or more likely pathogenic mutations were identified. In 593 patients (51%) a total of 885 variants of unknown clinical significance were found, including the patients who also carried a pathogenic or likely pathogenic mutation. Analysis of the different cardiomyopathy subtypes is ongoing and these results will be presented.
Conclusions: The results from this large single-center cohort show that NGS provides a conclusive or likely genetic diagnosis in 23% of unselected cardiomyopathy cases. The contribution of the large number of identified variants of unknown significance remains to be elucidated. In the near future, we hope to further characterize these variants by sharing our data with other laboratories both in the Netherlands and abroad and by performing both segregation studies and functional studies.
Author Disclosures: P.A. van der Zwaag: None. R.C. Niessen: None. L.G. Boven: None. Y.M. Hoedemaekers: None. R.J. Sinke: None. J.D. Jongbloed: None.
- © 2016 by American Heart Association, Inc.