Mutations and High-Risk Dilated and Arrhythmogenic Cardiomyopathies

Study Questions:

What is the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies?

Methods:

FLNC was studied by next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. The investigators identified a characteristic phenotype in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry.

Results:

The investigators identified 23 truncating mutations in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 individuals with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves with low voltages on electrocardiogram (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical stainings of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations.

Conclusions:

The authors concluded that truncating mutations in FLNC caused an overlapping phenotype of dilated and left dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death.

Perspective:

This study reports that truncating mutations in FLNC are associated with a characteristic cardiac phenotype that includes LV dilation with systolic dysfunction and myocardial fibrosis. Ventricular arrhythmias were extremely frequent, and families with these mutations showed a high incidence of sudden cardiac death. Further studies are needed to better understand the mechanisms linking truncating FLNC mutations to the clinical manifestations of these cardiomyopathies and to assess whether implantation of a cardiac defibrillator improves survival in carriers with myocardial fibrosis and ventricular arrhythmias.


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