A Finnish study finds evidence indicating the JPH2 gene to be causative in hypertrophic cardiomyopathy

This study¹ provides the first substantial evidence of the JPH2 gene associating with monogenic familial hypertrophic cardiomyopathy (HCM). The study ‘Heterozygous Junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure’ was published recently in PLOS ONE.

Hypertrophic cardiomyopathy is considered the most common form of inherited cardiomyopathies, estimated to affect one in 500 in general population. The condition may relate to severe heart failure and sudden cardiac death.

“The key impact to patient care is understanding the genetic cause behind hypertrophic cardiomyopathy better, in order to arrange adequate follow-up and treatment options, for example pacemaker or implantable cardioverter defibrillator, when needed. It also helps to evaluate the family members’ need for cardiac examinations”, explains cardiologist Tiina Heliö (MD, PhD) from Helsinki University Hospital Heart and Lung Center.

According to cardiologist Sari Vanninen (MD) from Heart Center, Tampere University Hospital, the decision to do this research stemmed from day-to-day clinical work, when patients with a clinical suspicion of cardiomyopathy were requested for genetic testing.

“A growing number of patients with poor heart function or remarkable hypertrophy and a JPH2 gene variant were observed and the patients and their family members were recruited to the study by their physicians. Information on the clinical histories of the patients and their family members was analyzed. This analysis was essential to the success of this study”, Vanninen says.

The study is part of a larger, long-lasting research project at Helsinki University Hospital Heart and Lung Center and University of Helsinki, Heart Center, and Blueprint Genetics, in collaboration with Tampere University Hospital with the focus on the genetics and phenotype of inherited cardiomyopathies.

In the study, a total of 20 individuals from nine different families affected with HCM were identified with JPH2 p.(Thr161Lys) variant. Although for years, several previous studies have suggested that JPH2 could harbor HCM-causing variants, the fundamental evidence supporting this hypothesis has been lacking.

“While JPH2 variants have been published in ClinVar database and multiple journal articles, they are often classified as variants of uncertain significance (VUS) due to a lack of family member surveillance and segregation studies, providing limited amount of information to the clinical community. In our daily interpretation work, we have re-classified the JPH2 p.(Thr161Lys) variant from VUS to likely pathogenic and further, to pathogenic. This information helps clinicians in establishing the correct diagnosis for their patient”, says Blueprint Genetics’ Chief Medical Officer and Laboratory Director Juha Koskenvuo (MD, PhD).

The impact of this finding is significant since it indicates a potentially new founder mutation in the Finnish population.

Summary of results:

• 20 individuals from 9 different families affected with HCM were identified with the JPH2(Thr161Lys) variant
• The study found 26 heterozygotes with the variant and the penetrance was 71% by age 60 and 100% by age 80.
• Co-segregation of the variant with a HCM phenotype was observed in 6 families.
• Collaboration between research, patient care, and genetic diagnostics allowed for an in-depth analysis of the clinical history of the patients and their families to be combined with observations and genetic testing results
• An extensive review of existing the JPH2 literature and a current status of JPH2 variants found in databases were included

Full study:
¹ Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure Vanninen SUM, Leivo K, Seppälä EH, Aalto-Setälä K, Pitkänen O, et al. (2018) Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure. PLOS ONE 13(9): e0203422. https://doi.org/10.1371/journal.pone.0203422

Further information:

Blueprint Genetics
Chief Medical Officer and Laboratory Director Juha Koskenvuo, juha.koskenvuo@blueprintgenetics.com

Helsinki University Central Hospital (HUCH)
Cardiologist Tiina Heliö, tiina.helio@hus.fi

Heart Center, Tampere University Hospital
Cardiologist Sari Vanninen, sari.vanninen@sydansairaala.fi