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
Affiliations
Róbert Sepp
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Lidia Hategan
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Beáta Csányi
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
János Borbás
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Annamária Tringer
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Eszter Dalma Pálinkás
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Viktória Nagy
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Hedvig Takács
Division of Non-Invasive Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Szeged, Semmelweis u. 8, H-6725 Szeged, Hungary
Gottsegen National Cardiovascular Center, Haller u. 29, H-1096 Budapest, Hungary
Attila Pálinkás
Elisabeth Hospital, Dr. Imre József u. 9, H-6800 Hódmezővásárhely, Hungary
Réka Faludi
Heart Institute, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary
Miklós Rábai
Division of Cardiology, First Department of Medicine, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary
Gábor Tamás Szabó
Division of Cardiology and Division of Clinical Physiology, Department of Cardiology, University of Debrecen, Móricz Zsigmond körút 22, H-4032 Debrecen, Hungary
Dániel Czuriga
Division of Cardiology and Division of Clinical Physiology, Department of Cardiology, University of Debrecen, Móricz Zsigmond körút 22, H-4032 Debrecen, Hungary
László Balogh
Division of Cardiology and Division of Clinical Physiology, Department of Cardiology, University of Debrecen, Móricz Zsigmond körút 22, H-4032 Debrecen, Hungary
Róbert Halmosi
Division of Cardiology, First Department of Medicine, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary
Attila Borbély
Division of Cardiology and Division of Clinical Physiology, Department of Cardiology, University of Debrecen, Móricz Zsigmond körút 22, H-4032 Debrecen, Hungary
Tamás Habon
Division of Cardiology, First Department of Medicine, Medical School, University of Pécs, Ifjúság útja 13, H-7624 Pécs, Hungary
Zoltán Hegedűs
Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Temesvári krt. 62, H-6726 Szeged, Hungary
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.
