Anatol J Cardiol. Ahead of Print: AJC-87292 | DOI: 10.14744/AnatolJCardiol.2023.2805

The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye

Veysel Oktay¹, Omaç Tüfekçioğlu², Dilek Çicek  Yılmaz³, Ersel Onrat⁴, Dilay Karabulut⁵, Murat Çelik⁶, Akif Serhat Balcıoğlu⁷, Mehmet Murat  Sucu⁸, Güllü Özdemir⁹, Hakkı Kaya¹⁰, Mehmet Kış¹¹, Barış Güven¹, Oktay Bağdatoğlu¹², Fatma Nihan  Turhan Çağlar⁵, Uygar Çağdaş  Yüksel⁶, İrfan Veysel  Düzen⁸, Ahmet Barutçu¹⁰, Özgüç Semih  Şimşir¹³, İbrahim Başarıcı¹⁴, Afşin Parspur¹⁵, Onur Dalgıç¹⁶, Fatma Özlem  Arıcan Özlük¹⁷, Mert Evlice¹⁸, Saim Sağ¹⁹, Muhammed Furkan  Deniz¹, Arslan Öcal⁶, Emine Gazi¹⁰, Taner Şen¹⁵, Osman Özdabakoğlu¹⁹, Nermin Bayar Çakıcı²⁰, Eren Ozan  Bakır²¹, Ayşegül Ülgen Kunak²², Gizem Çaylı¹³, Aybike Gül Taşdelen¹, Ercan Akşit¹⁰, Şefika Uslu Çil¹³, Hüseyin Onay^23
1Department of Cardiology, İstanbul University-Cerrahpaşa, Institute of Cardiology, İstanbul, Türkiye
²Clinic of Cardiology, Ankara City Hospital, Ankara, Türkiye
³Department of Cardiology, Faculty of Medicine, Mersin University, Mersin, Türkiye
⁴Department of Cardiology, Faculty of Medicine, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Türkiye
⁵Clinic of Cardiology, Dr. Sadi Konuk Training and Research Hospital, İstanbul, Türkiye
⁶Department of Cardiology, University of Health Sciences, Gülhane Faculty of Medicine, Ankara, Türkiye
⁷Department of Cardiology, Faculty of Medicine, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Türkiye
⁸Department of Cardiology, Faculty of Medicine, Gaziantep University, Gaziantep, Türkiye
⁹Clinic of Cardiology, Private Çekirge Heart and Arrhythmia Hospital, Bursa, Türkiye
¹⁰Department of Cardiology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
¹¹Department of Cardiology, Faculty of Medicine, Dokuz Eylül University, İzmir, Türkiye
¹²Department of Cardiology, İstanbul University-Cerrahpaşa, Institute of Cardiology, İstanbul, Türkiye
¹³Clinic of Nephrology, Ankara City Hospital, Ankara, Türkiye
¹⁴Clinic of Cardiology, Dr. Sadi Konuk Training and Research Hospital, İstanbul, Türkiye
¹⁵Department of Cardiology, University of Health Sciences, Gülhane Faculty of Medicine, Ankara, Türkiye
¹⁶Department of Cardiology, Faculty of Medicine, Gaziantep University, Gaziantep, Türkiye
¹⁷Department of Cardiology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
¹⁸Medical Affairs Rare Diseases, Sanofi, İstanbul, Türkiye
¹⁹Department of Cardiology, Faculty of Medicine, Akdeniz University, Antalya, Türkiye
²⁰Clinic of Cardiology, Kütahya University of Health Sciences, Evliya Çelebi Training and Research Hospital, Kütahya, Türkiye
²¹Clinic of Cardiology, Private Kardiya Cardiology Center, İzmir, Türkiye
²²Clinic of Cardiology, Private Cardiology Office, Bursa, Türkiye
²³Clinics of Cardiology, Adana City Hospital, Adana, Türkiye
²⁴Clinic of Cardiology, Acıbadem Bursa Hospital, Bursa, Türkiye
²⁵Department of Cardiology, İstanbul University-Cerrahpaşa, Institute of Cardiology, İstanbul, Türkiye
²⁶Department of Cardiology, University of Health Sciences, Gülhane Faculty of Medicine, Ankara, Türkiye
²⁷Department of Cardiology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
²⁸Clinic of Cardiology, Kütahya University of Health Sciences, Evliya Çelebi Training and Research Hospital, Kütahya, Türkiye
²⁹Clinic of Cardiology, Acıbadem Bursa Hospital, Bursa, Türkiye
³⁰Department of Cardiology, Antalya Training and Research Hospital, Antalya, Türkiye
³¹Department of Cardiology, Faculty of Medicine, Celal Bayar University, Manisa, Türkiye
³²Clinic of Cardiology, Private Medstar Topçular Hospital, Antalya, Türkiye
³³Medical Affairs Rare Diseases, Sanofi, İstanbul, Türkiye
³⁴Department of Cardiology, İstanbul University-Cerrahpaşa, Institute of Cardiology, İstanbul, Türkiye
³⁵Department of Cardiology, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
³⁶Medical Affairs Rare Diseases, Sanofi, İstanbul, Türkiye
³⁷Gene2Info Health Informatics, İstanbul, Türkiye; Multigen Genetic Diseases Diagnosis Center, İzmir, Türkiye

Background: Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy.

Methods: A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes.

Results: The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease.

Conclusions: Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.

Keywords: Hypertrophic cardiomyopathy, genetic mutation, Fabry disease, next-generation sequencing

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