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The novel desmin variant p.Leu115Ile is associated with a unique form of biventricular Arrhythmogenic Cardiomyopathy

Protonotarios, A; Brodehl, A; Asimaki, A; Jager, J; Quinn, E; Stanasiuk, C; Ratnavadivel, S; ... Lopes, LR; + view all (2020) The novel desmin variant p.Leu115Ile is associated with a unique form of biventricular Arrhythmogenic Cardiomyopathy. Canadian Journal of Cardiology 10.1016/j.cjca.2020.11.017. (In press).

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Abstract

BACKGROUND: Arrhythmogenic Cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC, but with insufficient evidence to support their pathogenicity. METHODS: We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutation were prospectively screened by whole exome sequencing. RESULTS: A single DES variant (p.Leu115Ile, c.343C>A) was identified in three index patients (2%). We assessed the clinical phenotypes within their families and confirmed co-segregation. One carrier required heart transplantation, two died suddenly and one died of non-cardiac causes. All cases had right and left ventricular (LV) involvement. LV late gadolinium enhancement was present in all and circumferential sub-epicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short proto-filaments and small fibrous aggregates. CONCLUSIONS: DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.

Type: Article
Title: The novel desmin variant p.Leu115Ile is associated with a unique form of biventricular Arrhythmogenic Cardiomyopathy
Location: England
DOI: 10.1016/j.cjca.2020.11.017
Publisher version: https://doi.org/10.1016/j.cjca.2020.11.017
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10117120
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