Elsevier

European Journal of Medical Genetics

Volume 54, Issue 6, November–December 2011, Pages e570-e575
European Journal of Medical Genetics

Original article
Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy

https://doi.org/10.1016/j.ejmg.2011.07.005Get rights and content

Abstract

Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 30 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a mutational screening on 4 DCM-causing genes (MYH7, TNNT2, TNNI3 and LMNA) was performed in a cohort of 105 unrelated DCM (64 familial cases and 41 sporadic cases) using a High Resolution Melting (HRM)/sequencing strategy. Screening of a highly conserved arginine/serine (RS)-rich region in exon 9 of RBM20 was also performed. Nineteen different mutations were identified in 20 index patients (19%), including 10 novels. These included 8 LMNA variants in 9 (8.6%) probands, 5 TNNT2 variants in 5 probands (4.8%), 4 MYH7 variants in 3 probands (3.8%), 1 TNNI3 variant in 1 proband (0.9%), and 1 RBM20 variant in 1 proband (0.9%). One proband was double-heterozygous. LMNA mutations represent the most prevalent genetic DCM cause. Most patients carrying LMNA mutations exhibit conduction system defects and/or cardiac arrhythmias. Our study also showed than prevalence of mutations affecting TNNI3 or the (RS)-rich region of RBM20 is lower than 1%. The discovery of novel DCM mutations is crucial for clinical management of patients and their families because pre-symptomatic diagnosis is possible and precocious intervention could prevent or ameliorate the prognosis.

Highlights

► Mutations in the LMNA gene represent the most prevalent genetic cause of DCM. ► Overall mutation detection rate of a cohort of 105 unrelated DCM patients was 19%. ► Prevalence of mutations affecting TNNI3 or the (RS)-rich region of RBM20 is lower than 1%. ► Sporadic DCM could have a genetic basis.

Introduction

Dilated cardiomyopathy (DCM), primarily characterized by left ventricular dilatation and impaired systolic function, is one of the leading causes of heart failure with high morbidity and mortality [1]. The prevalence is 1/2500 individuals. About 20–48% of DCM individuals had familial forms of the disease [1]. Disease-causing genes in familial DCM predominantly follow autosomal dominant inheritance patterns. The penetrance and presentation of familial DCM are highly variable concerning the functional impairment, the extent of cardiac involvement and the presence of other clinical manifestations. Over the past decade, private mutations were scattered among more than 30 genes encoding essentially sarcomeric, cytoskeletal, and nuclear proteins [2]. Available molecular data suggested that the three most prevalent genes involved in DCM are lamin A/C (LMNA, OMIM#: 150330), β-myosin heavy chain (MYH7, OMIM +160760), and cardiac troponin T (TNNT2, OMIM ∗191045) [2]. However, except an important mutational screening performed on a cohort of more than three hundred probands with familial or idiopathic dilated cardiomyopathy, no other cohort with a significant number (>100) of DCM Caucasian patients was investigated for mutations in these prevalent DCM genes [3], [4], [5], [6].

To provide new insights into the pathophysiology of dilated cardiomyopathy, a mutational screening on these prevalent DCM-causing genes was performed in a cohort of 105 unrelated DCM index probands (64 familial cases and 41 sporadic cases) using a High Resolution Melting (HRM)/sequencing strategy which was previously reported as an highly sensitive and high-throughput method to allow identification of mutations in the coding sequences of prevalent DCM genes [7], [8]. Additional TNNI3 screening (OMIM +191044) was also performed as mutations in this gene were recently reported in autosomal dominant DCM [9]. Finally, as a recent study suggested that mutations affecting a highly conserved arginine/serine (RS)-rich region in exon 9 of RBM20 could accounted for 3% of all DCM cases, we also undertook to study this exon in order to confirm its prevalence [10].

Section snippets

Subjects

The study included 105 unrelated index patients. Most of them were recruited from a general cardiology hospital. All probands underwent a comprehensive assessment including a clinical examination, ECG, echocardiogram and for most of the cases MRI, angiography and coronarography. High blood pressure, coronary disease, chronic excess of alcohol consumption and a systemic disease were excluded prior to genetic analysis. The clinical diagnostic criteria were established according to international

Global study population

Molecular screening was performed on a cohort constituted of 105 unrelated index probands who were recruited with an original clinical diagnosis of DCM. The mean onset age of this cohort was 37.3 ± 17.1 years. The presence of the disease was classified as familial in 64 cases (61.9%), and sporadic in 41 (38.1%) cases (Table 1). Mean age of onset was significantly different between sporadic and familial cases (41.5 ± 16.9 versus 30.7 ± 14.6 years; p = 0.0026). No statistical difference for onset

Discussion

The present study reports on the molecular screening of a population of 105 unrelated DCM cases. Mutational screening was performed in encoding regions of the 3 prevalent DCM-causing genes but also in TNNI3 and in exon 9 of RBM20. The overall mutation detection rate was 19% which is slightly higher than the mutation detection rate (13.2%) observed in a previous cohort of more than 300 DCM patients [3], [4], [5], [6]. This variation could be partially explained by differences in the clinical

Conflicts of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

This work was supported by PHRC 97061 and by French Ministry of Research (Diagnosis Network on Neuromuscular Diseases).

References (37)

  • M.R. Taylor et al.

    Natural history of dilated cardiomyopathy due to lamin A/C gene mutations

    J. Am. Coll. Cardiol.

    (2003)
  • L. Sfichi-Duke et al.

    Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins

    J. Mol. Cell. Cardiol.

    (2010)
  • S. Gowrisankar et al.

    Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications

    J. Mol. Diagn.

    (2010)
  • J. Mogensen et al.

    Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy

    J. Am. Coll. Cardiol.

    (2004)
  • L. Dellefave et al.

    The genetics of dilated cardiomyopathy

    Curr. Opin. Cardiol.

    (2010)
  • R.E. Hershberger et al.

    Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy

    Clin. Transl. Sci.

    (2008)
  • R.E. Hershberger et al.

    Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy

    Circ. Cardiovasc. Genet.

    (2010)
  • D. Li et al.

    Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy

    Clin. Transl. Sci.

    (2010)
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