Muscular dystrophy with arrhythmia caused by loss-of-function mutations in BVES
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Abstract
Objective To study the genetic and phenotypic spectrum of patients harboring recessive mutations in BVES.
Methods We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in BVES.
Results We identified 4 individuals from 3 families harboring homozygous LOF variants in BVES, the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of BVES through nonsense-mediated decay or through functional changes to the POPDC1 protein.
Conclusions We report the identification of homozygous LOF mutations in BVES, causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.
Glossary
- AV=
- atrioventricular;
- CADD=
- Combined Annotation-Dependent Depletion;
- CK=
- creatine kinase;
- EPS=
- electrophysiology study;
- EPS=
- electrophysiology study;
- ExAC=
- Exome Aggregation Consortium;
- IHC=
- immunohistochemical;
- KI=
- knock-in;
- LGMD=
- limb-girdle muscular dystrophy;
- LOF=
- loss of function;
- NMD=
- nonsense-mediated mRNA decay;
- PCCD=
- progressive cardiac conduction disorder;
- SND=
- sinus node dysfunction;
- WES=
- whole-exome sequencing
Footnotes
↵* These authors contributed equally to the manuscript as first authors.
↵† These authors contributed equally to the manuscript as last authors.
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.
The Article Processing Charge was funded by the authors.
- Received November 21, 2018.
- Accepted in final form February 12, 2019.
- Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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