Sudden death in hypertrophic cardiomyopathy: phenotype-genotype correlations

Relevance. Sudden cardiac death (SCD) risk assessment in patients with hypertrophic cardiomyopathy (HCM) is based solely on clinical and instrumental parameters. Still, there is an issue of inadequate prognosis of SCD risk requiring further investigations of individual risk factors. Objective of the present study was to assess genotype-phenotype associations in cohort of subjects with HCM who died from SCD, or had high risk of SCD with mutations in sarcomere protein genes. Materials and methods. The study comprised 29 individuals with HCM: 10 subjects died from SCD, 4 were successfully resuscitated and ICD implanted, and 15 individuals had a history complicated by SCD in first-line relatives. All patients were analyzed using clinical and instrumental data, and the search of mutations in protein-encoding sequences of sarcomere protein genes (using high throughput sequencing in 27 subjects, and Sanger automated sequencing in 2 subjects) was made. Results. Thirteen out of 18 (72,2%) HCM individuals with high risk of SCD by HCM-Risk SCD showed mutations and substitutions of unknown significance previously reported in literature including Val186Leu, Arg403Trp, Lys450Glu, Val606Met, Arg663Cys & Glu924Lys in MYH7; Asp610Asn combined with Pro1066Arg, Trp1214Arg, Gln1233*, Glu1265Val combined with Cys1266Arg in MYBPC3 and two new Tyr1043* & Arg1138fs in MYBPC3 gene. Six out of 11 subjects (54,5%) with low-to moderate SCD risk by HCM-Risk SCD showed mutations and substitutions of unknown significance previously reported including Arg1712Trp in MYH7 combined with the mutation of Arg502Gln in MYBPC3; Ser217Gly, Arg346His, Glu894Asp, in MYBPC3; Leu238Pro in ACTC1, and previously unknown substitution Trp1007fs in MYBPC3 gene. Conclusion. It seems feasible to include genetic data in SCD risk assessment, particularly for patients with low-to-moderate risk established using ESC-2014 HCM Risk-SCD score.

гипертрофическая кардиомиопатия, внезапная сердечная смерть, мутации, гены белков саркомеров, клинические проявления, секвенирование следующего поколения, hypertrophic cardiomyopathy, sudden cardiac death, mutations, sarcomere protein genes, clinical manifestations, sequencing of the next generation

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