Dilated cardiomyopathy: genetic causes and the strategy of DNA diagnostics
Abstract
Dilated cardiomyopathy is a myocardial disease with a steadily progressive course and a serious prognosis for life. Most adult forms of DCM are inherited by in an autosomal dominant manner. ESC (2016) Guidelines for the diagnosis and treatment of acute and chronic heart failure indicates that molecular genetic diagnostics is recommended for the genes where the rate of detectable mutations is reasonable for routine screening. More than 70 genes when mutated can lead to this disease, but the data on the mutation spectrum and their prevalence differ greatly.
The aim of this study was to reveal mutational spectrum in Russian adult patients with DCM, and to develop a strategy for DNA diagnosis and genetic counselling for such families.
Materials and methods. A clinical, instrumental and genetic examination was performed on 56 unrelated patients with non-ischemic DCM diagnosed after the age of 18 years. Clinical and instrumental evaluation included a general examination, collection of individual and family history, ECG, Echo CG, MSCT, MRI with gadolinium enhancement, coronary angiography, and endomyocardial biopsy. Genetic study included high-throughput semiconductor sequencing of the 81 genes, causative for DCM, based on Ion Torrent platform.
Results and discussion. The gender ratio (M : F) in the DCM cohort was 2 : 1; the average age of diagnosis was 37.4 y.o. The sporadic origin of DCM was confirmed in 30% probands, more than half of the patients mentioned cardiomyopathy in the family, and 30% probands had no traceble family history. 16 mutations were detected in 16 (28%) probands. Mutations identified in patients with isolated DCM were found in the MYH7, MyBPC3, TNNT2, SCN5A, LMNA, DES, DSP, and TTN genes. Patients with DCM, carriers of mutations in the DMD and NEBL genes, also had clinical signs of myopathy. All patients were interested in cascade familial screening and reproductive counselling.
Conclusion. Identification of the genetic cause of DCM in the family optimizes treatment options and allows developing an optimal reproductive strategy for the family. The two-step DNA diagnostic protocol for DCM seems to be cost-effective. The first step is to perform a mutation screening with the small targeted gene panel (MYH7, MyBPC3, TNNT2, SCN5A, LMNA, DES, and DSP). If mutations are detected, cascade family screening should be carried out. In the absence of diagnostic findings with a small panel or conflicting results of cascade family screening, it is recommended to perform whole exome sequencing.
Keywords:dilated cardiomyopathy, chronic heart failure, personalized therapy, Next Generation Sequencing, genetic councelling
For citation: Zaklyazminskaya E.V., Bukaeva A.A., Shestak A.G., Polyak M.E., Blagova O.V., Mershina E.A., Kotlukova N.P., Frolova Ju.V., Dzemeshkevich S.L. Dilated cardiomyopathy: genetic causes and the strategy of DNA diagnostics. Clin Experiment Surg. Petrovsky J. 2019; 7 (3): 44–53. doi: 10.24411/2308-1198-2019-13005 (in Russian)
Received 01.06.2019. Accepted 25.07.2019.
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