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Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.

Jones, EG; Mazaheri, N; Maroofian, R; Zamani, M; Seifi, T; Sedaghat, A; Shariati, G; Jamshidi, Y; Allen, HD; Wehrens, XHT; et al. Jones, EG; Mazaheri, N; Maroofian, R; Zamani, M; Seifi, T; Sedaghat, A; Shariati, G; Jamshidi, Y; Allen, HD; Wehrens, XHT; Galehdari, H; Landstrom, AP (2019) Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy. Sci Rep, 9 (1). p. 9038. ISSN 2045-2322 https://doi.org/10.1038/s41598-019-44987-6
SGUL Authors: Jamshidi, Yalda

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Abstract

Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Sci Rep
ISSN: 2045-2322
Language: eng
Dates:
DateEvent
21 June 2019Published
24 May 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
R01-HL117641National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01-HL089598National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01-HL091947National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
L40-HL129273National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
K08-HL136839National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
13EIA14560061American Heart Associationhttp://dx.doi.org/10.13039/100000968
PubMed ID: 31227780
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110983
Publisher's version: https://doi.org/10.1038/s41598-019-44987-6

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