Additional genetic variants in cardiomyopathy patients with the pathogenic PLN p.(Arg14del) founder variant

Aims: To evaluate the prevalence and clinical consequences of additional rare genetic variants in cardiomyopathy- and/or channelopathy-related genes in PLN p.(Arg14del) patients. Methods: In PLN p.(Arg14del) index patients (n = 160), additional rare genetic variants in cardiomyopathy- or channelopathy-related genes were collected. These variants were (re)classified as either variants of uncertain significance (VUS) or (likely) pathogenic ((L)P). VUS were further subcategorized in low, mid or high suspicion VUS. Cascade genetic testing results were studied in families with an additional (L)P variant. The occurrence and onset of malignant ventricular arrhythmias (MVA) or severe heart failure (HF)-related events in PLN index patients with and without additional (L)P variants were compared. In addition, extended genetic testing was performed in PLN relatives (n = 8) with major cardiac events <45 year. Results: In 6 % (6/106) of PLN index patients in whom targeted gene panel analysis was performed, an additional (L)P variant was identified. These patients showed a non-significant trend towards earlier onset of MVA or a severe HF-related event versus those without an additional variant. Incorporating VUS subclassification did not alter either of these trends. Two out of 8 PLN relatives with a major cardiac event <45 year had an additional P variant. Conclusion: Additional (L)P variants in established cardiomyopathy- or channelopathy-related genes were found in 6 % of PLN p.(Arg14del) index patients, which is higher than in control populations. These patients showed a trend towards earlier onset of MVA or HF-related symptoms.