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

Sari U M Vanninen,Samuel Myllykangas,Eija H Seppälä,Juha W Koskenvuo,Krista Leivo,Katriina Aalto-Setälä,Ismo Anttila,Tero-Pekka Alastalo,Tiina M Heliö,Piia Suursalmi,Antti-Pekka Annala,Olli Pitkänen,Vincenzo Lionetti

doi:10.1371/journal.pone.0203422

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.

Highlights

Hypertrophic cardiomyopathy (HCM) is considered the most common form of inherited cardiomyopathies estimated to affect one in 500 in general population [1]
We have identified the JPH2 p.(Thr161Lys) variant in nine Finnish index patients with HCM and have shown co-segregation of the variant with cardiomyopathy in six of these families
JPH2 is a cardiac specific member of the junctophilins and it has emerged as a potentially important regulator of excitation-contraction coupling in cardiomyocytes

Summary

Introduction

Hypertrophic cardiomyopathy (HCM) is considered the most common form of inherited cardiomyopathies estimated to affect one in 500 in general population [1]. Diagnosis of HCM is made by two-dimensional echocardiography showing hypertrophied, non-dilated left ventricle (LV) in the absence of other cardiac or systemic causes of hypertrophy such as aortic valve stenosis or hypertension [2]. HCM may manifest at any age but typically in the adulthood. Hereditary HCM is a dominant disorder, commonly associated with mutations in sarcomere genes. Phenocopies of HCM include Anderson-Fabry disease (galactosidase alpha, GLA), Danon disease (lysosomal-associated membrane protein 2, LAMP2), PRKAG2 related glycogen storage disease (protein kinase AMP-activated non-catalytic subunit gamma 2, PRKAG2), cardiac amyloidosis, neuromuscular diseases and malformation syndromes (Noonan spectrum syndromes).[6] Genetic diagnostics has proven as an effective strategy to differentiate between potential underlying causes and to rule out phenocopies. Accurate molecular genetic diagnosis helps to detect the genetic cause of those phenocopies that might require special therapy (e.g. enzyme replacement therapy) [7,8,9]

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