Gene-Panel Based Next Generation Sequencing (NGS) Greatly Improves Clinical Genetic Diagnostics in Inherited Cardiomyopathies

INTRODUCTION: NGS techniques can be successfully applied to find mutations underlying genetic cardiomyopathies. However, Exome Sequencing (ES) shows incomplete representation and coverage of exons, leading to clinically relevant mutations being missed. Thus, ES will, at least for now, coexist in clinical genetic diagnostics with other NGS-based strategies, such as gene-panel based resequencing. Therefore, we aimed at evaluating the yield of gene-panel based resequencing of 55 genes in cardiomyopathy patients referred to our department. METHODS: We constructed an enrichment kit targeting 55 cardiomyopathy genes and implemented this into routine diagnostics. We evaluated our first 162 patients: 47 fulfilled generally accepted clinical criteria for hypertrophic cardiomyopathy (HCM), 72 fulfilled the Mestroni criteria for dilated cardiomyopathy (DCM) and 3 were diagnosed with arrhythmogenic cardiomyopathy (ACM). In addition, 23, 11 and 6 cases showed signs of DCM, HCM and ACM, yet did not fulfill the formal criteria. Additional cosegregation analyses were performed to further support pathogenicity of potentially causal mutations. RESULTS: In the DCM cohort 40 pathogenic or likely pathogenic mutations were identified (55%; 40/72). Mutations in TTN were found in 14% of DCM patients (10/72). The yield in criteria positive HCM and ACM patients was 40% (17/43) and 33% (1/3). In patients not fully fulfilling criteria for DCM, HCM and ACM the yield was 52% (12/23), 36% (4/11) and 83% (5/6). In 13 % (21/162) of cases two or more (potentially) pathogenic mutations were identified. Results of cosegregation analyses supported pathogenicity of potentially causal mutations in 42 families. In 6 results argued against pathogenicity. CONCLUSIONS: Gene-panel based NGS results in a substantial increase in diagnostic yield for DCM patients compared to previous results of Sanger sequencing most prevalent genes (55% vs 20-25%). TTN mutations are most prevalent in DCM patients (14%). Higher diagnostic yields are achieved for patients fulfilling DCM and HCM criteria. Cosegregation analyses further support pathogenicity of potentially causal mutations. Together, our gene-panel based approach greatly improved genetic diagnostics in cardiomyopathies.