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

  1. Leila A. Gandaeva
  2. Olga S. Chumakova
  3. Yulia I. Davidova
  4. Roman P. Myasnikov
  5. Natalia A. Sonicheva-Paterson
  6. Alexander Pushkov
  7. Ilya Zhanin
  8. Daria Chudakova
  9. Alina Alekseeva
  10. Dmitry Demianov
  11. Olga V. Kulikova
  12. Maria M. Kudryavtseva
  13. Daria A. Nefedova
  14. Alina A. Hugaeva
  15. Olga V. Ivleva
  16. Marina I. Berseneva
  17. Alexander Gurshchenkov
  18. Sofia E. Andreeva
  19. Maria Y. Maslova
  20. Natalia S. Krylova
  21. Natalia G. Poteshkina
  22. Dmitry I. Zenchenko
  23. Natalia V. Tverdokhlib
  24. Victoria A. Korneva
  25. Sergey N. Tolstov
  26. Andrey P. Koval
  27. Olga M. Shestopalova
  28. Adilya H. Bukenbaeva
  29. Victoria Khvostikova-Ivanenko
  30. Svetlana E. Glova
  31. Marina V. Gordeeva
  32. Elizaveta A. Yabzhanova
  33. Tatiana A. Romanova
  34. Svetlana N. Nasonova
  35. Anastasia Kruglova
  36. Olga Shchagina
  37. Aleksander Polyakov
  38. Dmitry A. Zateyshchikov
  39. Elena N. Basargina
  40. Sergey Kutsev
  41. Andrey Fisenko
  42. Kirill V. Savostyanov
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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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  1. Version published to 10.1101/2025.11.05.25339569 on medRxiv