The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes

Róbert Sepp; Lidia Hategan; Beáta Csányi; János Borbás; Annamária Tringer; Eszter Dalma Pálinkás; Viktória Nagy; Hedvig Takács; Dóra Latinovics; Noémi Nyolczas; Attila Pálinkás; Réka Faludi; Miklós Rábai; Gábor Tamás Szabó; Dániel Czuriga; László Balogh; Róbert Halmosi; Attila Borbély; Tamás Habon; Zoltán Hegedűs; István Nagy

doi:10.3390/diagnostics12051132

The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes

Diagnostics (Basel). 2022 May 3;12(5):1132. doi: 10.3390/diagnostics12051132.

Authors

Róbert Sepp¹, Lidia Hategan¹, Beáta Csányi¹, János Borbás¹, Annamária Tringer¹, Eszter Dalma Pálinkás¹, Viktória Nagy¹, Hedvig Takács¹, Dóra Latinovics², Noémi Nyolczas^{3

4}, Attila Pálinkás⁵, Réka Faludi⁶, Miklós Rábai⁷, Gábor Tamás Szabó⁸, Dániel Czuriga⁸, László Balogh⁸, Róbert Halmosi^{7

9}, Attila Borbély⁸, Tamás Habon⁷, Zoltán Hegedűs^{10

11}, István Nagy^{2

12}

Affiliations

¹ Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary.
² SeqOmics Biotechnology Ltd., Vállalkozók útja 7, H-6782 Mórahalom, Hungary.
³ Gottsegen National Cardiovascular Center, Haller u. 29, H-1096 Budapest, Hungary.
⁴ Military Hospital-State Health Center, Róbert Károly körút 44, H-1134 Budapest, Hungary.
⁵ Elisabeth Hospital, Dr. Imre József u. 9, H-6800 Hódmezővásárhely, Hungary.
⁶ Heart Institute, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary.
⁷ Division of Cardiology, First Department of Medicine, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary.
⁸ Division of Cardiology and Division of Clinical Physiology, Department of Cardiology, University of Debrecen, Móricz Zsigmond körút 22, H-4032 Debrecen, Hungary.
⁹ Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary.
¹⁰ Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, H-6726 Szeged, Hungary.
¹¹ Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
¹² Institute of Biochemistry, Biological Research Center, Eötvös Loránd Research Network, Temesvári krt. 62, H-6726 Szeged, Hungary.

Abstract

Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium most commonly caused by mutations in sarcomeric genes. We aimed to perform a nationwide large-scale genetic analysis of a previously unreported, representative HCM cohort in Hungary. A total of 242 consecutive HCM index patients (127 men, 44 ± 11 years) were studied with next generation sequencing using a custom-designed gene-panel comprising 98 cardiomyopathy-related genes. A total of 90 patients (37%) carried pathogenic/likely pathogenic (P/LP) variants. The percentage of patients with P/LP variants in genes with definitive evidence for HCM association was 93%. Most of the patients with P/LP variants had mutations in MYBPC3 (55 pts, 61%) and in MYH7 (21 pts, 23%). Double P/LP variants were present in four patients (1.7%). P/LP variants in other genes could be detected in ≤3% of patients. Of the patients without P/LP variants, 46 patients (19%) carried a variant of unknown significance. Non-HCM P/LP variants were identified in six patients (2.5%), with two in RAF1 (p.Leu633Val, p.Ser257Leu) and one in DES (p.Arg406Trp), FHL1 (p.Glu96Ter), TTN (p.Lys23480fs), and in the mitochondrial genome (m.3243A>G). Frameshift, nonsense, and splice-variants made up 82% of all P/LP MYBPC3 variants. In all the other genes, missense mutations were the dominant form of variants. The MYBPC3 p.Gln1233Ter, the MYBPC3 p.Pro955ArgfsTer95, and the MYBPC3 p.Ser593ProfsTer11 variants were identified in 12, 7, and 13 patients, respectively. These three variants made up 36% of all patients with identified P/LP variants, raising the possibility of a possible founder effect for these mutations. Similar to other HCM populations, the MYBPC3 and the MYH7 genes seemed to be the most frequently affected genes in Hungarian HCM patients. The high prevalence of three MYBPC3 mutations raises the possibility of a founder effect in our HCM cohort.

Keywords: genetic analysis; genetic variant; hypertrophic cardiomyopathy.

Grants and funding

This study was supported by Economic Development and Innovation Operational Program Grants (GINOP 2.3.2-15-2016-00048, GINOP-2.3.3-15-2016-00039, and GINOP-2.1.2-8.1.4-16-2017-00186); by the National Research, Development, and Innovation Office (grant No: 2018-1.1.1-MKI-2018-00098); as well as by a Research Fund from the University of Debrecen. R.S is a recipient of the “Hetényi Géza” grant of the Faculty of Medicine, University of Szeged.