AİLESEL HİPERTROFİK KARDİYOMİYOPATİDE SARKOMERİK GEN VARYANTLARININ ANİ KARDİYAK ÖLÜM RİSKİNİN ÖNGÖRÜLMESİNE KATKISI

Abstract

Amaç: Hipertrofik kardiyomiyopati (HKM), ani kardiyak ölümün (AKÖ) nedenlerinden biridir. Bu çalışmada, HKM’de en sık mutasyon bulunan üç sarkomerik gende, AKÖ için yüksek riskli patojenik varyantların belirlenmesi amaçlandı. Gereç ve Yöntem: Çalışmaya, AKÖ ve/veya HKM için aile öyküsü olan 12 yetişkin HKM’li indeks vaka ve 31 aile üyesi dahil edildi. Tüm katılımcılar, kardiyolojik olarak değerlendirildi. MYH7, MYBPC3 ve TNNT2 genlerinin ekzonik bölgeleri, CorTAG HCM1 dizileme sistemi kullanılarak analiz edildi. Bulgular: HKM’li indeks vakaların 8’inde, amino asit değişimine neden olan 6 farklı patojenik varyant bulundu. Bunlardan beşinin, MYH7 genindeki Val698Ala, Arg719Trp, Met822Leu ve Arg- 663Cys (üç vakada) ve TNNT2 genindeki Arg102Trp değişimlerinin daha önce tanımlanmış yanlış anlamlı patojenik varyantlar olduğu belirlendi. İleri yaşta AKÖ öyküsü olan bir HKM ailesinde, MYBPC3 geninde Tyr525Asn ve c.*27-21G>A varyantlar bileşik heterozigot olarak ilk defa tanımlandı. Bu varyantlar, Türk popülasyonu kontrol örneklerinde (n=777) saptanmadı. Sonuç: Bu çalışmada, AKÖ öyküsü olan bir HKM ailesinde yeni varyantlar tanımlandı. Ancak, HKM ailelerinde saptanan patojenik varyantlar ile AKÖ riski arasında net bir ilişki bulunamadı.

Keywords

• Sarkomerik gen varyantı
• ailesel hipertrofik kardiyomiyopati
• ani kardiyak ölüm

CONTRIBUTION OF SARCOMERIC GENE VARIANTS TO THE PREDICTION OF SUDDEN CARDIAC DEATH RISK IN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

Abstract

Objective: Hypertrophic cardiomyopathy (HCM) is one of sudden cardiac death (SCD) causes. This study aimed to identify high-risk pathogenic variants for SCD in the three sarcomeric genes with the most frequent mutations in HCM. Material and Method: The study included 12 adult HCM index cases with a family history of SCD and/or HCM, and 31 of their family members. All the participants were evaluated with detailed cardiac examinations. The exonic regions of the MYH7, MYBPC3 and TNNT2 genes were analysed using CorTAG HCM1 resequencing arrays. Results: Six pathogenic variants causing amino acid substitutions were found in 8 of the index cases with HCM. Five of them were identified as previously defined missense variants of Val698Ala, Arg719Trp, Met822Leu and Arg663Cys (in three cases) in the MYH7 gene, and Arg102Trp in the TNNT2 gene. For the first time in an HCM family with a history of late-onset SCD, Tyr525Asn and c.*27-21G> A variants in the MYBPC3 gene were identified as compound heterozygous. These variants were not present in control subjects (n=777) from the Turkish population. Conclusion: In this study, novel variants in the MYBPC3 gene were identified in an HCM family with SCD history. However, there was no clear association between pathogenic variants and the risk of SCD.

Keywords

• Sarcomeric gene variant
• familial hypertrophic cardiomyopathy
• sudden cardiac death

References

1. 1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995;92:785-9.
2. 2. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 2012;60(8):705-15.
3. 3. Jordà P, García-Álvarez A. Hypertrophic cardiomyopathy: Sudden cardiac death risk stratification in adults. Glob Cardiol Sci Pract. 2018;2018(3):25.
4. 4. Jarcho JA, McKenna W, Pare JA, Solomon SD, Holcombe RF, Dickie S, et al. Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. N Engl J Med 1989;321:1372-8.
5. 5. Rodríguez JE, McCudden CR, Willis MS. Familial hypertrophic cardiomyopathy: basic concepts and future molecular diagnostics. Clin Biochem 2009;42(9):755-65.
6. 6. Meder B, Haas J, Keller A, Heid C, Just S, Borries A, et al. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet. 2011;4(2):110-22.
7. 7. Millat G, Chanavat V, Rousson R. Evaluation of a new NGS method based on a custom AmpliSeq library and Ion Torrent PGM sequencing for the fast detection of genetic variations in cardiomyopathies. Clin Chim Acta 2014;433:266-71.
8. 8. Waldmüller S, Schroeder C, Sturm M, Scheffold T, Imbrich K, Junker S, et al. Targeted 46-gene and clinical exome sequencing for mutations causing cardiomyopathies. Mol Cell Probes 2015; 29:308-14.

9. 9. Mendes de Almeida R, Tavares J, Martins S, Carvalho T, Enguita FJ, Brito D, et al. Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with hypertrophic cardiomyopathy. PLoS One 2017;12(8):e0182946.
10. 10. Bottillo I, D’Angelantonio D, Caputo V, Paiardini A, Lipari M, De Bernardo C, et al. Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. Gene 2016;577:227-35.
11. 11. Ho CY, Charron P, Richard P, Girolami F, Van Spaendonck- Zwarts KY, Pinto Y. Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res 2015;105:397-408.
12. 12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al; ACMG Laboratory Quality Assurance Committee. 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;17(5):405-24.
13. 13. Kucukkates E, Ersanli M, Gultekin N, Sayhan N, Mutlu H, Kalfoglu E, et al. Clinical Investigations 403Arg-Gln Missence Point Mutation of ß-Myosin-Heavy-Chain in Hypertrophic Cardiomyopathy Families in a Diverse Turkish Population and its Relation with Sudden Cardiac Death. Turk Kardiyol Dern Ars 1999;27:664-71.
14. 14. Cam FS, Terzioglu O, Sagan A, Nalbantgil I, Ozerkan F, Ozdamar M, et al. Detection of Arg403Gln, Arg453Cys, Arg719Trp and Arg719Gln Mutations in the ß-Myosin Heavy Chain Gene (ß-Mhc) Causing to Hypertrophic Cardiomyopathy. Turk Kardiyol Dern Ars 2002;30:30-5.
15. 15. Hallioglu Kilinc O, Giray D, Bisgin A, Tug Bozdogan S, Karpuz D. Familial hypertrophic cardiomyopathy: A case with a new mutation in the MYBPC3 gene. Turk Kardiyol Dern Ars 2017;45:450-3.
16. 16. Christiaans I, Nannenberg EA, Dooijes D, Jongbloed RJ, Michels M, Postema PG, et al. Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands. Neth Heart J 2010;18(5):248-54.
17. 17. Landstrom AP, Ackerman MJ. Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy. Circulation 2010;122(23):2441-9; discussion 2450. [CrossRef]
18. 18. Mohiddin SA, Begley DA, McLam E, Cardoso JP, Winkler JB, Sellers JR, Fananapazir L. Utility of genetic screening in hypertrophic cardiomyopathy: prevalence and significance of novel and double (homozygous and heterozygous) betamyosin mutations. Genet Test 2003;7(1):21-7.
19. 19. Fujino N, Konno T, Hayashi K, Hodatsu A, Fujita T, Tsuda T, et al. Impact of systolic dysfunction in genotyped hypertrophic cardiomyopathy. Clin Cardiol 2013;36(3):160- 5.
20. 20. Wang J, Smith PJ, Krainer AR, Zhang MQ. Distribution of SR protein exonic splicing enhancer motifs in human proteincoding genes. Nucleic Acids Res 2005;33(16):5053-62.
21. 21. Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet 2013;50(4):228-39.
22. 22. Girolami F, Olivotto I, Passerini I, Zachara E, Nistri S, Re F, et al. A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy. J Cardiovasc Med (Hagerstown) 2006;7(8):601-7.
23. 23. Bortot B, Athanasakis E, Brun F, Rizzotti D, Mestroni L, Sinagra G, Severini GM. High-throughput genotyping robot-assisted method for mutation detection in patients with hypertrophic cardiomyopathy. Diagn Mol Pathol 2011;20(3):175-9.
24. 24. Anan R, Greve G, Thierfelder L, Watkins H, McKenna WJ, Solomon S, Vecchio C, Shono H, et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994;93(1):280-5.
25. 25. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet 2005;42(10):e59.
26. 26. Van Driest SL, Jaeger MA, Ommen SR, Will ML, Gersh BJ, Tajik AJ, Ackerman MJ. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44(3):602-10.
27. 27. Restrepo-Cordoba AM, Campuzano O, Ripoll-Vera T, Cobo- Marcos M, Mademont-Soler I, Gámez JM, et al. Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data. J Cardiovasc Transl Res 2017;10(1):35-46.
28. 28. Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C. A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart 2012;98(8):625-30.
29. 29. Jiang J, Wakimoto H, Seidman JG, Seidman CE. Allelespecific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science 2013;342(6154):111-4.
30. 30. Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenic gene mutation in human embryos. Nature 2017;548(7668):413-9.