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. doi: 10.1038/s41598-019-44987-6.
Edward G Jones  1 ,  Neda Mazaheri  2  3 ,  Reza Maroofian  4 ,  Mina Zamani  2  3 ,  Tahereh Seifi  2  3 ,  Alireza Sedaghat  5 ,  Gholamreza Shariati  3 ,  Yalda Jamshidi  4 ,  Hugh D Allen  1  6 ,  Xander H T Wehrens  6  7 ,  Hamid Galehdari  8 ,  Andrew P Landstrom  9  10  11
Affiliations
  • 1. Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas, United States.
  • 2. Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
  • 3. Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.
  • 4. Molecular and Clinical Sciences Institute, St George's University of London, London, United Kingdom.
  • 5. Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
  • 6. Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, United States.
  • 7. Department of Molecular Physiology and Biophysics, Department of Medicine, Section of Cardiology, Center for Space Medicine, Baylor College of Medicine, Houston, Texas, United States.
  • 8. Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran. [email protected].
  • 9. Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas, United States. [email protected].
  • 10. Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, United States. [email protected].
  • 11. Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, United States. [email protected].
PMID: 31227780 DOI: 10.1038/s41598-019-44987-6
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.