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Abstract

Dilated Cardiomyopathy (DCM) is a leading cause for heart failure characterized by an enlarged ventricular cavity causing systolic dysfunction. Although a multifactorial disease, DCM has been attributed to gene mutations in approximately 30-50% of cases. However, the full spectrum of the genetic basis of DCM remains elusive. QCRC-IGC is a Doha-centered intercontinental consortium comprising teams from Egypt, Greece, UK, Italy and the USA. It aims at discovering novel gene variants implicated in DCM pathogenesis and/or progression, through the establishment of a multinational DCM patient cohort and the genetic investigation of over 170 genes (including all DCM genes) using the cutting-edge technology of Next Generation Sequencing (NGS). Herein we present the genetic screening of sixteen DCM patients (5 sporadic and 11 familial), as confirmed by echocardiography and/or MRI, who did not have a history of alcoholism or coronary angiography findings. Over 1,600 variants were detected in each patient, the vast majority of which represent well documented benign polymorphisms. Forty variants had never been reported before, involving the genes: TTN, SYNE1, MYH6, ALMS1, SDHA, MYPN, LAMA2, TPM1, PLEC, FOXD4, ILK, SGCB and DSP. TTN mutations are being detected in 27% of DCM cases. Of particular interest is the polymorphism observed in the gene DSP, as it was detected in two affected sisters of the same family, it represents the only common potentially pathogenic variant shared between them, and it is bioinformatically predicted to lead to a dysfunctional protein product. Importantly, other mutations in DSP have been previously associated with DCM as well as ARVC. Significant findings of immediate research and ultimately diagnostic/prognostic value are beginning to emerge. Additionally, the discovery of novel pathogenic mutations would unveil promising new therapeutic targets. QCRC is currently intensifying the patient recruitment process at the clinical level, while focusing on the molecular characterization of the emerging novel variants using in silico modeling, induced pluripotent stem cells, and systems biology approaches.

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/content/papers/10.5339/qfarf.2013.BIOP-064
2013-11-20
2019-11-14
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarf.2013.BIOP-064
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