Martina Lipari1, Ewa Wypasek2,3, Marek Karpiński2, Lidia Tomkiewicz-Pajak2,4, Luigi Laino1, Francesco Binni1, Diana Giannarelli5, Paweł Rubiś2,4, Paweł Petkow-Dimitrow6,7, Anetta Undas2,7, Paola Grammatico1, Irene Bottillo8. 1. Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy 2. John Paul II Hospital, Kraków, Poland 3. Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Kraków, Poland 4. Department of Cardiac Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland 5. Biostatistical Unit, Regina Elena National Cancer Institute, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy 6. 2nd Department of Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland 7. Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland 8. Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy; i.bottillo@gmail.com
Abstract
INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES: This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS: Twenty‑nine Polish patients were analyzed by a next generation sequencing panel including 404 cardiovascular genes. RESULTS: Pathogenic variants were found in 41% of the patients, with ultra‑ rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3. CONCLUSIONS: This report expands the mutational spectrum and the inheritance pattern of HCM.
INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES: This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS: Twenty‑nine Polish patients were analyzed by a next generation sequencing panel including 404 cardiovascular genes. RESULTS: Pathogenic variants were found in 41% of the patients, with ultra‑ rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3. CONCLUSIONS: This report expands the mutational spectrum and the inheritance pattern of HCM.
Authors: 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 Journal: Diagnostics (Basel) Date: 2022-05-03