Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel TTN Frameshift Mutation

Abstract

Dilated cardiomyopathy (DCM) is the leading indication for heart transplantation. <i>TTN</i> gene truncating mutations account for about 25% of familial DCM cases and for 18% of sporadic DCM cases. The clinical relevance of specific variants in <i>TTN</i> has been difficult to determine because of the sheer size of the protein for which <i>TTN</i> encodes, as well as existing extensive genetic variation. Clinicians should communicate novel clinically-relevant variants and genotype-phenotype associations, so that animal studies evaluating the molecular mechanisms are always conducted with a focus on clinical significance. In the present study, we report for the first time the novel truncating heterozygous variant NM_001256850.1:c.72777_72783del (p.Phe24259Leufs*51) in the <i>TTN</i> gene and its association with DCM in a family with sudden death. This variant occurs in the A-band region of the sarcomere, in a known mutational hotspot of the gene. Truncating titin variants that occur in this region are the most common cause of DCM and have been rarely reported in asymptomatic individuals, differently from other pathogenic <i>TTN</i> gene variants. Further studies are warranted to better understand this particular clinically-relevant variant.