Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 4, Pages 980-991Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt494
Keywords
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Funding
- Institut National de la Sante Et de la Recherche Medicale
- Association Institut de Myologie
- Assistance Public-Hopitaux de Paris
- Leducq Foundation
- MRC
- DZHK
- BMBF
- Centre de Recherche du CHU Ste-Justine
- Iowa Wellstone Muscular Dystrophy Cooperative Research Center [U54, NS053672]
- Fonds Quebec de recherche pour la Nature et Technology
- British Heart Foundation [PG/11/127/29322] Funding Source: researchfish
- Medical Research Council [G0200496, G0600251, MR/J010456/1] Funding Source: researchfish
- MRC [MR/J010456/1, G0600251] Funding Source: UKRI
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Core myopathies (CM), the main non-dystrophic myopathies in childhood, remain genetically unexplained in many 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 CM families with homozygous mutations of the TTN gene. TTN encodes titin, a giant protein of striated muscles. Recently, heterozygous TTN truncating mutations have also been reported as a major cause of dominant dilated cardiomyopathy. However, relatively few TTN mutations and phenotypes are known, and titin pathophysiological role in cardiac and skeletal muscle conditions is incompletely understood. We analyzed a series of 23 families with congenital CM and 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, EmeryDreifuss 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 that CM are associated with a large range of heart conditions of which TTN mutations are a major cause, thereby expanding the TTN mutational and phenotypic spectrum. Additionally, our results suggest titin kinase implication in cardiac morphogenesis and demonstrate that heterozygous TTN truncating mutations may not manifest unless associated with a second mutation, reassessing the paradigm of their dominant expression.
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