Atlas of the clinical genetics of human dilated cardiomyopathy.
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Haas Jan, Frese Karen S, Peil Barbara, Kloos Wanda, Keller Andreas, Nietsch Rouven, Feng Zhu, Müller Sabine, Kayvanpour Elham, Vogel Britta, Sedaghat-Hamedani Farbod, Lim Wei-Keat, Zhao Xiaohong, Fradkin Dmitriy, Köhler Doreen, Fischer Simon, Franke Jennifer, Marquart Sabine, Barb Ioana, Li Daniel Tian, Amr Ali, Ehlermann Philipp, Mereles Derliz, Weis Tanja, Hassel Sarah, Kremer Andreas, King Vanessa, Wirsz Emil, Isnard Richard, Komajda Michel, Serio Alessandra, Grasso Maurizia, Syrris Petros, Wicks Eleanor, Plagnol Vincent, Lopes Luis, Gadgaard Tenna, Eiskjær Hans, Jørgensen Mads, Garcia-Giustiniani Diego, Ortiz-Genga Martin, Crespo-Leiro Maria G, Deprez Rondal H Lekanne Dit, Christiaans Imke, van Rijsingen Ingrid A, Wilde Arthur A, Waldenstrom Anders, Bolognesi Martino, Bellazzi Riccardo, Mörner Stellan, Bermejo Justo Lorenzo, Monserrat Lorenzo, Villard Eric, Mogensen Jens, Pinto Yigal M, Charron Philippe, Elliott Perry, Arbustini Eloisa, Katus Hugo A, Meder Benjamin
Аннотация
METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes.
CONCLUSION: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.