Comprehensive Genetic Study of Russian Hypertrophic Cardiomyopathy Identifies MYBPC3 c.3697C>T as the Predominant Variant in Pediatric and Adult Cohorts

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Abstract Background. The genetic etiology of hypertrophic cardiomyopathy (HCM) is complex and population-specific, yet Russian HCM patients remain understudied. Methods. Between 2015-2025, unrelated pediatric and adult HCM patients were genotyped in a single laboratory. Children were sequenced with a 404-gene panel and adults with a 17-gene panel. Genotype-phenotype correlations were assessed for carriers of the most frequent variant, MYBPC3 c.3697C>T , and compared with patients harboring other MYPBC3 variants. Haplotype analysis explored its potential founder effect. Results. The cohort comprised 315 children (mean age 11.7 years, 61% male; 127 infant-onset) and 3,409 adults (mean age 47.5 years, 58% male). Genotype-positive rates were 89% in children and 28% in adults. Sarcomeric and RASopathy variants accounted for 35% and 33% of infant-onset, 56% and 17% of childhood-onset, and 22% and 0.4% of adult-onset genotyped cases, respectively. The MYBPC3 c.3697C>T variant was identified in 83 patients (2.2%). Compared with controls (n = 85), carriers (n = 58) more often had left ventricular ejection fraction below 50% (9% vs. 1%, p = 0.038), left atrial dilation (76% vs. 47%, p = 0.001), and supraventricular arrythmias (45% vs. 25%, p = 0.027). Pediatric carriers showed no left ventricular outflow tract obstruction (0% vs. 29%, p = 0.024) and fewer conduction disturbances (13% vs. 48%, p = 0.029). Intervention rates and outcomes were similar across ages. Haplotype analysis was inconclusive for founder effect. Conclusions. The genetic spectrum of HCM in Russian population largely mirrors Western data. Within MYBPC3 -associated HCM, the c.3697C>T variant is linked to a milder, nonobstructive pediatric phenotype and increased hypokinetic progression in adults but does not influence overall outcomes. Its high prevalence likely reflects a combination of founder and recurrent mutational events.

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