Doubly Heterozygous LMNA and TTN Mutations Revealed by Exome Sequencing in a Severe Form of Dilated Cardiomyopathy

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2013 Mar 7

PMID 23463027

Citations 55

Authors

Roberta Roncarati

Chiara Viviani Anselmi

Peter Krawitz

Giovanna Lattanzi

Yskert von Kodolitsch

Andreas Perrot

Elisa Di Pasquale

Laura Papa

Paola Portararo

Marta Columbaro

Alberto Forni

Giuseppe Faggian

Gianluigi Condorelli

Peter N Robinson

Affiliations

Soon will be listed here.

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.

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