Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Abstract

Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

A Rising Titan:TTNReview and Mutation Update

“…Table S1) [Gerull et al, 2002;Itoh-Satoh et al, 2002;Matsumoto et al, 2005;Gerull et al, 2006;Liu et al, 2008;Herman et al, 2012;Yoskovitz et al, 2012;Roncarati et al, 2013]. DCM is a heterogeneous group of cardiac diseases characterized by ventricular dilatation and reduced systolic function [Richardson et al, 1996;Itoh-Satoh et al, 2002].…”

Titin mutations: the fall of Goliath

“…The authors noted that many of the truncated isoforms lacked the M-line region, which is thought to be responsible for mechanosensing, and therefore could impair a normal regulation of sarcomeric force. More recently, using a whole-exome sequencing technique, Roncarati et al [40] described an association between a newly described mutation in TTN (Leu4855Phe) and a previously known lamin A/C gene (LMNA) mutation. Several members of the Italian family where the study was conducted presented a wide array of cardiological symptoms, ranging from mild dyspnea to severe congestive heart failure requiring heart transplantation.…”

Gigantic Business

“…90 The majority of the TTN mutations found in DCM patients are truncating mutations within A-band titin, but I-band mutations and a few Z-disk and M-band (including TK) mutations have also been reported ( Figure 4). 83,84,[90][91][92][93][94][95][96] These mutations include mostly nonsense and frameshift as well as splicing variants. Some patients with a titin mutation present with both cardiac and skeletal muscle disease, 91,96 but often it is unknown whether in patients with a cardiac phenotype the skeletal muscles are affected as well.…”