Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy

• Verfasst von: Parikh, Victoria N. [VerfasserIn]
• Verfasst von: Sedaghat-Hamedani, Farbod [VerfasserIn]
• Verfasst von: Meder, Benjamin [VerfasserIn]
• Titel: Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy
• Verf.angabe: Parikh Victoria N., Caleshu Colleen, Reuter Chloe, Lazzeroni Laura C., Ingles Jodie, Garcia John, McCaleb Kristen, Adesiyun Tolulope, Sedaghat-Hamedani Farbod, Kumar Saurabh, Graw Sharon, Gigli Marta, Stolfo Davide, Dal Ferro Matteo, Ing Alexander Y., Nussbaum Robert, Funke Birgit, Wheeler Matthew T., Hershberger Ray E., Cook Stuart, Steinmetz Lars M., Lakdawala Neal K., Taylor Matthew R.G., Mestroni Luisa, Merlo Marco, Sinagra Gianfranco, Semsarian Christopher, Meder Benjamin, Judge Daniel P., Ashley Euan
• E-Jahr: 2019
• Jahr: 15 Mar 2019
• Umfang: ? S.
• Fussnoten: Gesehen am 14.08.2019
• Titel Quelle: Enthalten in: Circulation / Heart failure
• Ort Quelle: Philadelphia, Pa. : Lippincott, Williams & Wilkins, 2008
• Jahr Quelle: 2019
• Band/Heft Quelle: 12(2019,3) Artikel-Nummer e005371, ? Seiten
• ISSN Quelle: 1941-3297
• DOI: doi:10.1161/CIRCHEARTFAILURE.118.005371
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1671359747

Abstract

BackgroundVariants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined.Methods and ResultsTo define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy.ConclusionsOur data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.