New insights on genetic diagnostics in cardiomyopathy and arrhythmia patients gained by stepwise exome data analysis

Konstantinos Kolokotronis, Natalie Pluta, Eva Klopocki, Erdmute Kunstmann, Daniel Messroghli, Christoph Maack, Shai Tejman-Yarden, Michael Arad, Simone Rost, Brenda Gerull

Research output: Contribution to journalArticlepeer-review


Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.

Original languageEnglish
Article number2168
Pages (from-to)1-15
Number of pages15
JournalJournal of Clinical Medicine
Issue number7
StatePublished - Jul 2020


  • Candidate genes
  • Cardiogenetics
  • Cardiomyopathy
  • Targeted gene panel
  • Whole exome sequencing


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