Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Aim: Idiopathic cardiomyopathy is often genetic in origin, typically autosomal dominant, and restrictive cardiomyopathy (RCM) is the rarest form. Clinically, RCM prognosis is poor with most patients requiring heart transplant due to impaired diastolic function leading to heart failure. In some cases, desminopathy is also observed, whereby desmin protein aggregates in the myocardium. Many genes are known to be involved in cardiomyopathy, and we sought to find the pathogenic mutation of a four-generation family with RCM and desminopathy. Methods: We employed whole exome sequence analysis of four RCM patients from the family, to identify the underlying pathogenic mutation(s). Results: Analysis of the exome data led to identification of two putative pathogenic variants. One, a nonsense mutation in ADD3, encoding adducin 3, was found in the proband and his affected daughter, but not other family members. The other was a missense mutation (G1546S) in the gene encoding filamin C (FLNC), found in all of the affected individuals. Both of these proteins interact with proteins involved in sarcomere function, and are expressed in both heart and skeletal muscle. FLNC has recently been implicated as a cardiomyopathy gene, but ADD3 has not at this point. Conclusion: We present bioinformatic analyses that suggest that the FLNC variant is the major pathogenic variant affecting this family, but cannot rule out some contribution of the ADD3 mutation in at least two patients.