Original articleClinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy
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)
- et al.
Cardiomyopathy familial dilated
Orphanet J. Rare Dis.
(2006) - et al.
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy
Am. Heart J.
(2008) - et al.
Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene
Clin. Biochem.
(2009) - et al.
Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy
J. Am. Coll. Cardiol.
(2009) - et al.
Long-term outcome and risk stratification in dilated cardiolaminopathies
J. Am. Coll. Cardiol
(2008) - et al.
High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics
Am. Heart J.
(2007) - et al.
Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy
J. Card. Fail.
(2002) - et al.
Clinical features of hypertrophic cardiomyopathy caused by an Arg278Cys missense mutation in the cardiac troponin T gene
Am. J. Cardiol.
(2004) - et al.
Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease
J. Card. Fail.
(2001) - et al.
Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease
J. Am. Coll. Cardiol.
(2002)
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations
J. Am. Coll. Cardiol.
Cardiomyopathy-causing deletion K210 in cardiac troponin T alters phosphorylation propensity of sarcomeric proteins
J. Mol. Cell. Cardiol.
Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications
J. Mol. Diagn.
Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy
J. Am. Coll. Cardiol.
The genetics of dilated cardiomyopathy
Curr. Opin. Cardiol.
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy
Clin. Transl. Sci.
Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy
Circ. Cardiovasc. Genet.
Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy
Clin. Transl. Sci.
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