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.

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Jones, Edward G

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Mazaheri, Neda

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Maroofian, Reza

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Zamani, Mina

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Seifi, Tahereh

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Sedaghat, Alireza

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Shariati, Gholamreza

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Jamshidi, Yalda

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Allen, Hugh D

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Wehrens, Xander HT

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Galehdari, Hamid

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Landstrom, Andrew P

dc.date.accessioned

2020-04-01T13:26:48Z

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2020-04-01T13:26:48Z

dc.date.issued

2019-06-21

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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.

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10.1038/s41598-019-44987-6

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2045-2322

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2045-2322

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https://hdl.handle.net/10161/20293

dc.language

eng

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Springer Science and Business Media LLC

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Scientific reports

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10.1038/s41598-019-44987-6

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Science & Technology

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Multidisciplinary Sciences

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Science & Technology - Other Topics

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GENETIC-VARIATION

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SEQUENCE VARIANTS

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HEART

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CLASSIFICATION

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MUTATION

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EXOME

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RECOMMENDATIONS

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STATEMENT

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SOCIETY

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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

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1

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School of Medicine

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Cell Biology

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Pediatrics, Cardiology

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Duke

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Basic Science Departments

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Pediatrics

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Clinical Science Departments

pubs.publication-status

Published

pubs.volume

9

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