Recessive TTN truncating mutations define novel forms of core myopathy with heart disease

Abstract

Coremyopathies(CM), themainnon-dystrophicmyopathiesinchildhood, remaingeneticallyunexplainedinmany cases. Heart disease is not considered part of the typical CM spectrum. No congenital heart defect has been reported, and childhood-onset cardiomyopathy has been documented in only two CMfamilies with homozygous mutations of theTTNgene.TTNencodestitin,agiantprotein of striatedmuscles.Recently,heterozygousTTNtruncatingmutationshavealsobeenreportedasamajorcauseofdominantdilatedcardiomyopathy. However,relatively fewTTNmutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletalmuscle conditions is incompletely understood.We analyzed a series of 23 families with congenital CMand primary heart disease using TTN M-line-targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We identified seven novel homozygous or compound heterozygous TTN mutations (five in the M-line, five truncating) in 17% patients. Heterozygous parents were healthy. Phenotype analysis identified four novel titinopathies, including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy or arthrogryposis. Additionally, in vitro studies documented the first-reported absence of a functional titin kinase domain in humans, leading to a severe antenatal phenotype.We establish thatCMare associatedwitha large rangeofheart conditionsofwhichTTNmutations are amajor cause, thereby expandingtheTTN mutational and phenotypic spectrum.Additionally, our results suggest titin kinase implicationin cardiacmorphogenesis and demonstrate that heterozygous TTNtruncatingmutationsmay notmanifest unless associatedwith a second mutation, reassessing the paradigmof their dominant expressiondiseases. © The Author 2013. Published by Oxford University Press. All rights reserved.