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

Leila A. Gandaeva; Чумакова Ольга Сергеевна; Yulia I. Davidova; Roman P. Myasnikov; Natalia Sonicheva‐Paterson; Alexander A. Pushkov; Жанин Илья Сергеевич; Daria A. Chudakova; Alina Alekseeva; D.S. Demianov; Olga V. Kulikova; Maria M. Kudryavtseva; D. A. Nefedova; А.А. Хугаева; Olga V. Ivleva; Marina I. Berseneva; А. В. Гурщенков; S. E. Andreeva; M. Yu. Maslova; Natalia S. Krylova; Н. Г. Потешкина; Dmitry I. Zenchenko; Natalia V. Tverdokhlib; Victoria Korneva; Sergey N. Tolstov; Andrey P. Koval; Olga M. Shestopalova; Adilya H. Bukenbaeva; Viktoria Hvostikova-Ivanenko; Глова Светлана Евгеньевна

doi:10.1101/2025.11.05.25339569

Genetic & Genomic MedicinemedRxivNov 5, 2025

Preprint

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

Leila A. Gandaeva iD, Чумакова Ольга Сергеевна iD, Yulia I. Davidova, Roman P. Myasnikov iD, Natalia Sonicheva‐Paterson iD, Alexander A. Pushkov iD, Жанин Илья Сергеевич iD, Daria A. Chudakova iD, Alina Alekseeva, D.S. Demianov iD, Olga V. Kulikova iD, Maria M. Kudryavtseva iD, D. A. Nefedova iD, А.А. Хугаева, Olga V. Ivleva iD, Marina I. Berseneva iD, А. В. Гурщенков iD, S. E. Andreeva iD, M. Yu. Maslova iD, Natalia S. Krylova iD, Н. Г. Потешкина iD, Dmitry I. Zenchenko, Natalia V. Tverdokhlib iD, Victoria Korneva iD, Sergey N. Tolstov iD, , Kirill Victorovich Savostyanov iD

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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