Dataset Information

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.

ABSTRACT: During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.

SUBMITTER: Vanninen SUM

PROVIDER: S-EPMC6147424 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.

Vanninen Sari U M SUM Leivo Krista K Seppälä Eija H EH Aalto-Setälä Katriina K Pitkänen Olli O Suursalmi Piia P Annala Antti-Pekka AP Anttila Ismo I Alastalo Tero-Pekka TP Myllykangas Samuel S Heliö Tiina M TM Koskenvuo Juha W JW

PloS one 20180920 9

During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requir ...[more]

PMID: 30235249

Similar Datasets

Project description:BackgroundTranscriptional remodeling is known to contribute to heart failure (HF). Targeting stress-dependent gene expression mechanisms may represent a clinically relevant gene therapy option. We recently uncovered a salutary mechanism in the heart whereby JP2 (junctophilin-2), an essential component of the excitation-contraction coupling apparatus, is site-specifically cleaved and releases an N-terminal fragment (JP2NT [N-terminal fragment of JP2]) that translocates into the nucleus and functions as a transcriptional repressor of HF-related genes. This study aims to determine whether JP2NT can be leveraged by gene therapy techniques for attenuating HF progression in a preclinical pressure overload model.MethodsWe intraventricularly injected adeno-associated virus (AAV) (2/9) vectors expressing eGFP (enhanced green fluorescent protein), JP2NT, or DNA-binding deficient JP2NT (JP2NTΔbNLS/ARR) into neonatal mice and induced cardiac stress by transaortic constriction (TAC) 9 weeks later. We also treated mice with established moderate HF from TAC stress with either AAV-JP2NT or AAV-eGFP. RNA-sequencing analysis was used to reveal changes in hypertrophic and HF-related gene transcription by JP2NT gene therapy after TAC. Echocardiography, confocal imaging, and histology were performed to evaluate heart function and pathological myocardial remodeling following stress.ResultsMice preinjected with AAV-JP2NT exhibited ameliorated cardiac remodeling following TAC. The JP2NT DNA-binding domain is required for cardioprotection as its deletion within the AAV-JP2NT vector prevented improvement in TAC-induced cardiac dysfunction. Functional and histological data suggest that JP2NT gene therapy after the onset of cardiac dysfunction is effective at slowing the progression of HF. RNA-sequencing analysis further revealed a broad reversal of hypertrophic and HF-related gene transcription by JP2NT overexpression after TAC.ConclusionsOur prevention- and intervention-based approaches here demonstrated that AAV-mediated delivery of JP2NT into the myocardium can attenuate stress-induced transcriptional remodeling and the development of HF when administered either before or after cardiac stress initiation. Our data indicate that JP2NT gene therapy holds great potential as a novel therapeutic for treating hypertrophy and HF.

Project description:BackgroundReduction of 30-day all-cause readmissions for heart failure (HF) has become an important quality-of-care metric for health care systems. Many hospitals have implemented quality improvement programs designed to reduce 30-day all-cause readmissions for HF. Electronic medical record (EMR)-based measures have been employed to aid in these efforts, but their use has been largely adjunctive to, rather than integrated with, the overall effort.ObjectivesWe hypothesized that a comprehensive EMR-based approach utilizing an HF dashboard in addition to an established HF readmission reduction program would further reduce 30-day all-cause index hospital readmission rates for HF.MethodsAfter establishing a quality improvement program to reduce 30-day HF readmission rates, we instituted EMR-based measures designed to improve cohort identification, intervention tracking, and readmission analysis, the latter 2 supported by an electronic HF dashboard. Our primary outcome measure was the 30-day index hospital readmission rate for HF, with secondary measures including the accuracy of identification of patients with HF and the percentage of patients receiving interventions designed to reduce all-cause readmissions for HF.ResultsThe HF dashboard facilitated improved penetration of our interventions and reduced readmission rates by allowing the clinical team to easily identify cohorts with high readmission rates and/or low intervention rates. We significantly reduced 30-day index hospital all-cause HF readmission rates from 18.2% at baseline to 14% after implementation of our quality improvement program ( P = .045). Implementation of our EMR-based approach further significantly reduced 30-day index hospital readmission rates for HF to 10.1% ( P for trend = .0001). Daily time to screen patients decreased from 1 hour to 15 minutes, accuracy of cohort identification improved from 83% to 94.6% ( P = .0001), and the percentage of patients receiving our interventions, such as patient education, also improved significantly from 22% to 100% over time ( P < .0001).ConclusionsIn an institution with a quality improvement program already in place to reduce 30-day readmission rates for HF, an EMR-based approach further significantly reduced 30-day index hospital readmission rates.

Dataset Information

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.

Publications

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets