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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.

Publication ,  Journal Article
Jones, EG; Mazaheri, N; Maroofian, R; Zamani, M; Seifi, T; Sedaghat, A; Shariati, G; Jamshidi, Y; Allen, HD; Wehrens, XHT; Galehdari, H; Landstrom, AP
Published in: Sci Rep
June 21, 2019

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.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 21, 2019

Volume

9

Issue

1

Start / End Page

9038

Location

England

Related Subject Headings

  • Muscle Proteins
  • Middle East
  • Membrane Proteins
  • Infant, Newborn, Diseases
  • Infant, Newborn
  • Humans
  • Homozygote
  • Exome Sequencing
  • Cohort Studies
  • Cardiomyopathy, Dilated
 

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Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., … Landstrom, A. P. (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), 9038. https://doi.org/10.1038/s41598-019-44987-6
Jones, Edward G., Neda Mazaheri, Reza Maroofian, Mina Zamani, Tahereh Seifi, Alireza Sedaghat, Gholamreza Shariati, et al. “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, no. 1 (June 21, 2019): 9038. https://doi.org/10.1038/s41598-019-44987-6.
Jones EG, Mazaheri N, Maroofian R, Zamani M, Seifi T, Sedaghat A, Shariati G, Jamshidi Y, Allen HD, Wehrens XHT, Galehdari H, Landstrom AP. 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. 2019 Jun 21;9(1):9038.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 21, 2019

Volume

9

Issue

1

Start / End Page

9038

Location

England

Related Subject Headings

  • Muscle Proteins
  • Middle East
  • Membrane Proteins
  • Infant, Newborn, Diseases
  • Infant, Newborn
  • Humans
  • Homozygote
  • Exome Sequencing
  • Cohort Studies
  • Cardiomyopathy, Dilated