Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy

Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1161/CIRCHEARTFAILURE.118.00537...
Journal or Publication Title: Circulation: Heart Failure
Volume: 12
Number: 3
Date: 2019
Divisions: Cardio Genomics
Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1161/CIRCHEARTFAILURE.118.005371
ISSN: 1941-3289
Date Deposited: 17 Dec 2020 03:26
Abstract:

Background: Variants 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 Results: To 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.

Conclusions: Our 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.

Keywords: RNA splicing; arrhythmias, cardiac; cardiomyopathies; genetics.

Creators:
Creators
Email
Parikh, Victoria N.
UNSPECIFIED
Caleshu, Colleen
UNSPECIFIED
Reuter, Chloe
UNSPECIFIED
Lazzeroni, Laura C.
UNSPECIFIED
Ingles, Jodie
UNSPECIFIED
Garcia, John
UNSPECIFIED
McCaleb, Kristen
UNSPECIFIED
Adesiyun, Tolulope
UNSPECIFIED
Sedaghat-Hamedani, Farbod
UNSPECIFIED
Kumar, Saurabh
UNSPECIFIED
Graw, Sharon
UNSPECIFIED
Gigli, Marta
UNSPECIFIED
Stolfo, Davide
UNSPECIFIED
Dal Ferro, Matteo
UNSPECIFIED
Ing, Alexander Y.
UNSPECIFIED
Nussbaum, Robert
UNSPECIFIED
Funke, Birgit
UNSPECIFIED
Wheeler, Matthew T.
UNSPECIFIED
Hershberger, Ray E.
UNSPECIFIED
Cook, Stuart
UNSPECIFIED
Steinmetz, Lars M.
UNSPECIFIED
Lakdawala, Neal K.
UNSPECIFIED
Taylor, Matthew R.G.
UNSPECIFIED
Mestroni, Luisa
UNSPECIFIED
Merlo, Marco
UNSPECIFIED
Sinagra, Gianfranco
UNSPECIFIED
Semsarian, Christopher
UNSPECIFIED
Meder, Benjamin
UNSPECIFIED
Judge, Daniel P.
UNSPECIFIED
Ashley, Euan
UNSPECIFIED
Last Modified: 17 Dec 2020 03:26
URI: https://eprints.centenary.org.au/id/eprint/261

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