Семейная кардиомиопатия, обусловленная мутацией в гене RBM20: многообразие клинических проявлений фенотипа. Клиническое наблюдение

Генетические причины все чаще оказываются ответственными за развитие внезапной смерти у молодых людей. В 2009 г. список генов, злокачественные мутаций в которых ассоциированы с развитием дилатационной кардиомиопатии (ДКМП) и внезапной сердечной смертью (ВСС), пополнился геном RBM20. Высокий риск злокачественных желудочковых нарушений ритма сердца при RBM20-ассоциированной ДКМП сделал пациентов с этой генетической патологией потенциальными кандидатами на имплантацию устройств для первичной профилактики ВСС. Представленное клиническое наблюдение демонстрирует разнообразие клинических фенотипов, обусловленных злокачественной патогенной мутацией в гене RBM20 в одной семье, варьирующих от случаев внезапной смерти, до малосимптомных форм. Кроме того, данный случай позволил впервые обнаружить наличие удлинения интервала QT за счет слияния с U-волной у носителей этой злокачественной семейной мутации. Удлинение интервала QT потенциально может вносить дополнительный вклад в формирование условий для развития желудочковых аритмий и риска ВСС у пациентов с этой редкой генетической патологией.

1. Mendis SPP, Norrving B. Global Atlas on Cardiovascular Disease Prevention and Control. Geneva: World Health Organization; 2011.

2. Maron BJ, Gohman TE, Aeppli D. Prevalence of sudden cardiac death during competitive sports activities in Minnesota high school athletes. J Am Coll Cardiol. 1998;32: 1881-1884. https://doi.org/10.1016/s0735-1097(98)00491-4.

3. van der Werf C, Hendrix A, Birnie E et al. Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): a community-based intervention study. Europace. 2016;18(4): 592-601. https://doi.org/10.1093/europace/euv059.

4. Skinner JR, Winbo A, Abrams D et al. Channelopathies that lead to Sudden Cardiac Death: Clinical and Genetic Aspects. Heart, Lung and Circulation. 2019;28(1): 22-30. https://doi.org/10.1016/j.hlc.2018.09.007.

5. Peters S, Johnson R, Birch S et al. Familial Dilated Cardiomyopathy. Heart Lung Circ. 2020 Apr;29(4): 566-574. https://doi.org/10.1016/j.hlc.2019.11.018.

6. Morales A, Hershberger RE. Genetic evaluation of dilated cardiomyopathy. Curr Cardiol Rep. 2013;15: 375.

7. Jordan E, Peterson L, Ai T et al. Evidence-Based Assessment of Genes in Dilated Cardiomyopathy. Circulation. 2021;144(1): 7-19. https://doi.org/10.1161/CIRCULATIONAHA.120.053033.

8. Wells QS, Becker JR, Su YR et al. Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree With Familial Dilated Cardiomyopathy Circ Cardiovasc Genet. 2013;6: 317-326. https://doi.org/10.1161/CIRCGENETICS.113.000011.

9. Zeppenfeld K, Tfelt-Hansen J, Marta de Riva et al, ESC Scientific Document Group , 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC) Endorsed by the Association for European Paediatric and Congenital Cardiology (AEPC), European Heart Journal. 2022;43(40): 3997-4126, https://doi.org/10.1093/eurheartj/ehac262.

10. Lepeshkin E., Sueawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation. 1952;6(3): 378-88. https://doi.org/10.1161/01.cir.6.3.378.

11. Obeyesekere MN, Klein GJ, Modi S, et al. How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2011;4(6): 958-64. https://doi.org/10.1161/CIRCEP.111.965947.

12. Ackerman MJ, Khositseth A, Tester DJ et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002;77(5): 413-21. https://doi.org/10.4065/77.5.413.

13. Sy RW, van der Werf C, Chattha IS et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011 15;124(20): 2187-94. https://doi.org/10.1161/CIRCULATIONAHA.111.028258.

14. Pinto YM, Elliott PM, Arbustini E et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37(23): 1850-8. https://doi.org/10.1093/eurheartj/ehv727.

15. Arbelo E, Protonotarios A, Gimeno JR et al ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37): 3503-3626. https://doi.org/10.1093/eurheartj/ehad194.

16. Schwartz PJ, Moss AJ, Vincent GM et al. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88(2): 782-4. https://doi.org/10.1161/01.cir.88.2.782.

17. Brauch KM, Karst ML, Herron KJ, et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J Am Coll Cardiol.2009;54: 930-941.

18. Li D, Morales A, Gonzalez-Quintana J, et al. Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. Clin Transl Sci. 2010;3(3): 90-7. https://doi.org/10.1111/j.1752-8062.2010.00198.x.

19. Wells QS, Becker JR, Su YR et al. Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. Circ Cardiovasc Genet. 2013;6(4): 317-26. https://doi.org/10.1161/CIRCGENETICS.113.000011.

20. Akinrinade O, Ollila L, Vattulainen S, et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J. 2015;36(34): 2327-37. https://doi.org/10.1093/eurheartj/ehv253.

21. Herman DS, Lam L, Taylor MR et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7): 619-28. https://doi.org/10.1056/NEJMoa1110186.

22. Lennermann D, Backs J, van den Hoogenhof MMG. New Insights in RBM20 Cardiomyopathy. Curr Heart Fail Rep. 2020;17(5): 234-246. https://doi.org/10.1007/s11897-020-00475-x.

23. Ihara K, Sasano T, Hiraoka Y et al. A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice. Sci Rep. 2020;10(1): 17894. https://doi.org/10.1038/s41598-020-74800-8.

24. Hey TM, Rasmussen TB, Madsen T et al. Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. Circ Heart Fail. 2019;12(3): e005700. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005700.

25. Kornienko J, Rodríguez-Martínez M, Fenzl K et al. Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3. Nat Commun. 2023;14(1): 4312. https://doi.org/10.1038/s41467-023-39965-6.

26. Koelemen J, Gotthardt M, Steinmetz LM et al. RBM20-Related Cardiomyopathy: Current Understanding and Future Options. J Clin Med. 2021;10(18): 4101. https://doi.org/10.3390/jcm10184101.

27. Parikh VN, Caleshu C, Reuter C et al. Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circ Heart Fail. 2019;12(3): e005371. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005371.