Spectrum of desmosomal gene variations in patients with arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary myocardial disease with a high risk of sudden cardiac death. The most common genetic forms of the disease are associated with desmosomal gene mutations.

Aim. To study the prevalence of desmosomal forms of ARVC and to analyze variations in the PKP2, DSG2, DSP, DSC2 and JUP genes in a sample of Russian patients with ARVC.

Material and methods. Included patients with ARVC underwent resting electrocardiography (ECG), 24-hour Holter ECG monitoring, echocardiography, chest x-ray, myocardial biopsy (if indicated), contrast-enhanced cardiac magnetic resonance imaging. All patients underwent medical genetic counseling. Mutations in the PKP2, DSG2, DSP, DSC2, and JUP genes was detected using highthroughput sequencing on the IonTorrent platform, followed by Sanger sequencing of uncovered gene regions. The pathogenicity of identified genetic variations was assessed according to modern guidelines.

Results. ARVC was established in 80 Russian unrelated patients. More than half of the probands (57%) in the study sample had definite diagnosis of ARVC, while 30% and 13% — borderline and possible ARVC, respectively. A positive family history of heart disease and/or SCD was noted in 30%. Genetic variants of pathogenicity class IV-V were detected in 15 (18,75%) probands in the PKP2, DSG2, DSP genes. The detection of genetic variants of pathogenicity class IV-V was different in the subgroups of patients with varying degrees of diagnosis reliability: 13 probands (28,3%) in the subgroup with definite ARVC and 2 probands (8,3%) in the subgroup with borderline ARVC. No genotype-positive probands were found in the subgroup with possible ARVC. Variations of unknown clinical significance were found in 13 (16,25%) probands.

Conclusion. The diagnostic yield of the desmosomal genes PKP2, DSG2, DSP, DSC2, and JUP was 19% with initial diagnosis of ARVC. The detection of mutations was significantly higher in patients with definite ARVC and severe disease manifestations.

1. Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: An international task force consensus statement. Eur Heart J. 2015;36(46):3227-37. doi:10.1093/eurheartj/ehv162.

2. James CA, Calkins H. Arrhythmogenic right ventricular cardiomyopathy: Evidence for progression increases. Eur. Heart J. 2020:14(41):1411-3. doi:10.1093/eurheartj/ehz705.

3. Oomen AWGJ, Semsarian C, Puranik R, et al. Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy: Progress and Pitfalls. Hear. Lung Circ. 2018;27(11):1310-7. doi:10.1016/j.hlc.2018.03.023.

4. Calkins H, Corrado D, Marcus F. Risk stratification in arrhythmogenic right ventricular cardiomyopathy. Circulation. 2017:21(136):2068-82. doi:10.1161/CIRCULATIONAHA.117.030792.

5. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: A United States experience. Circulation. 2005;112(25):3823-32. doi:10.1161/CIRCULATIONAHA.105.542266.

6. Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982:65(2):384-98.

7. Tabib A, Loire R, Chalabreysse L. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. ACC Current Journal Review. 2004:3(4):3000-5. doi:10.1161/01.CIR.0000108396.65446.21.

8. Gordeeva MV, Mitrofanova LB, Pakhomov AV, et al. Arrhythmogenic right ventricular cardiomyopathy/dysplasia as a cause of sudden cardiac death of young adults. J Arrhythmology. 2012;69:38-48. (In Russ.)

9. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). The Lancet. 2000:355(9221):2119-24. doi:10.1016/S01406736(00)02379-5.

10. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J. Am. Acad. Dermatol. 1998:3(39):418-21. doi:10.1016/s01909622(98)70317-2.

11. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet. 2000:9(18):2761-6. doi:10.1093/hmg/9.18.2761.

12. Rampazzo A. Regulatory mutations in transforming growth factor-β3 gene involved in arrhythmogenic right ventricular cardiomyopathy. Cardiovasc. Res. 2012:2(96):191-4. doi:10.1016/j.cardiores.2004.10.005.

13. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019:16(11):e301-e372. doi:10.1016/j.hrthm.2019.05.007.

14. Cirillo N. 150th anniversary series: Desmosomes in physiology and disease. Cell Commun.

15. Adhes. 2014:2(21):85-8. doi:10.3109/15419061.2013.863281.

16. Garcia-Gras E, Lombardi R, Giocondo MJ, et al. Suppression of canonical Wnt/βcatenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. The Journal of clinical investigation. 2006:116(7):2012-21. doi:10.1172/JCI27751.

17. Chelko SP, Asimaki A, Andersen P, et al. Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight. 2016:1(5):e85923. doi:10.1172/jci.insight.85923.

18. Sato PY, Coombs W, Lin X, et al. Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc. Circ Res. 2011:109(2):193-201. doi:10.1161/CIRCRESAHA.111.247023.

19. Leo-Macias A, Agullo-Pascual E, Sanchez-Alonso JL, et al. Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc. Nat Commun. 2016:7:10342. doi:10.1038/ncomms10342.

20. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. Eur. Heart J. 2010:31(7):806-14. doi:10.1093/eurheartj/ehq025.

21. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 2015:5(17):405-24. doi:10.1038/gim.2015.30.

22. Ryzhkova OP, Kardymon OL, Prohorchuk EB, et al. Guidelines for the interpretation of massive parallel sequencing variants. Meditsinskaya genetica. 2019;18(2):3-23. (In Russ.) doi:10.25557/2073-7998.2019.02.3-23.

23. Abou Tayoun AN, Pesaran T, DiStefano MT, et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum. Mutat. 2018:11(39):1517-24. doi:10.1002/humu.23626.

24. Corrado D, Perazzolo Marra M, Zorzi A, et al. Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria. Int J Cardiol. 2020;319:106-14. doi:10.1016/j.ijcard.2020.06.005.

25. Baturova MA, Haugaa KH, Jensen HK, et al. Atrial fibrillation as a clinical characteristic of arrhythmogenic right ventricular cardiomyopathy: experience from the Nordic ARVC Registry. International journal of cardiology. 2020:298:39-43. doi:10.1016/j.ijcard.2019. 07.086.

26. Groeneweg JA, Bhonsale A, James CA, et al. Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. Circ. Cardiovasc. Genet. 2015:3(8):437-46.

27. Ohno S, Nagaoka I, Fukuyama M, et al. Age-dependent clinical and genetic characteristics in Japanese patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circ. J. 2013:6(77):1534-42. doi:10.1253/circj.CJ-66-0185.

28. Bauce B, Rampazzo A, Basso C, et al. Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations. Heart Rhythm. 2011:8(11):1686-95.

29. Sen-Chowdhry S, Syrris P, Ward D, et al. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007:115(13):1710-20.

30. Lopez-Ayala JM, Pastor-Quirante F, Gonzalez-Carrillo J, et al. Genetics of myocarditis in arrhythmogenic right ventricular dysplasia. Heart Rhythm. 2015:12(4):766-73. doi:10.1016/j.hrthm.2015.01.001.

31. Blagova OV, Lutokhina YA, Kogan EA, et al. Myocarditis in right ventricular arrhythmogenic dysplasia/cardiomyopathy: frequency, role in phenotype development, results of treatment. Clinical and Experimental Surgery. Petrovsky Journal. 2020;8(3):59-72. (In Russ.) doi:10.33029/2308-1198-2020-8-359-72.

32. Lutokhina YA, Blagova OV, Nedostup AV, et al. Contribution of concomitant myocarditis to the development of various clinical types of arrhythmogenic right ventricular cardiomyopathy. Cardiovascular Therapy and Prevention. 2021;20(5):2781. (In Russ.) doi:10.15829/1728-8800-2021-2781.

33. Kapplinger JD, Landstrom AP, Salisbury BA, et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J. Am. Coll. Cardiol. 2011:23(57):2317-27. doi:10.1016/j.jacc.2010.12.036.

34. David KL, Best RG, Brenman LM, et al. Patient re-contact after revision of genomic test results: points to consider–a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019:21:769-71. doi:10.1038/s41436-018-0391-z.

35. El Mecky J, Johansson L, Plantinga M, et al. Reinterpretation, reclassification, and its downstream effects: challenges for clinical laboratory geneticists. BMC Med Genomics. 2019:12(1):170. doi:10.1186/s12920-019-0612-6.