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.
dc.contributor.author | Jones, Edward G | |
dc.contributor.author | Mazaheri, Neda | |
dc.contributor.author | Maroofian, Reza | |
dc.contributor.author | Zamani, Mina | |
dc.contributor.author | Seifi, Tahereh | |
dc.contributor.author | Sedaghat, Alireza | |
dc.contributor.author | Shariati, Gholamreza | |
dc.contributor.author | Jamshidi, Yalda | |
dc.contributor.author | Allen, Hugh D | |
dc.contributor.author | Wehrens, Xander HT | |
dc.contributor.author | Galehdari, Hamid | |
dc.contributor.author | Landstrom, Andrew P | |
dc.date.accessioned | 2020-04-01T13:26:48Z | |
dc.date.available | 2020-04-01T13:26:48Z | |
dc.date.issued | 2019-06-21 | |
dc.date.updated | 2020-04-01T13:26:46Z | |
dc.description.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. | |
dc.identifier | 10.1038/s41598-019-44987-6 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | ||
dc.language | eng | |
dc.publisher | Springer Science and Business Media LLC | |
dc.relation.ispartof | Scientific reports | |
dc.relation.isversionof | 10.1038/s41598-019-44987-6 | |
dc.subject | Science & Technology | |
dc.subject | Multidisciplinary Sciences | |
dc.subject | Science & Technology - Other Topics | |
dc.subject | GENETIC-VARIATION | |
dc.subject | SEQUENCE VARIANTS | |
dc.subject | HEART | |
dc.subject | CLASSIFICATION | |
dc.subject | MUTATION | |
dc.subject | EXOME | |
dc.subject | RECOMMENDATIONS | |
dc.subject | STATEMENT | |
dc.subject | SOCIETY | |
dc.subject | FAMILY | |
dc.title | 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. | |
dc.type | Journal article | |
duke.contributor.orcid | Landstrom, Andrew P|0000-0002-1878-9631 | |
pubs.begin-page | 9038 | |
pubs.issue | 1 | |
pubs.organisational-group | School of Medicine | |
pubs.organisational-group | Cell Biology | |
pubs.organisational-group | Pediatrics, Cardiology | |
pubs.organisational-group | Duke | |
pubs.organisational-group | Basic Science Departments | |
pubs.organisational-group | Pediatrics | |
pubs.organisational-group | Clinical Science Departments | |
pubs.publication-status | Published | |
pubs.volume | 9 |
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