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

Sari U M Vanninen1, Krista Leivo2, Eija H Seppälä3

  • 1Heart Center, Tampere University Hospital, Tampere, Finland.

Plos One
|September 21, 2018
PubMed

Insights

A new Finnish mutation in the JPH2 gene, p.(Thr161Lys), causes atypical hypertrophic cardiomyopathy (HCM). This variant shows significant penetrance and is linked to left ventricular hypertrophy and conduction abnormalities in affected families.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Human Genetics

Background:

  • Mutations in sarcomere genes are the primary cause of hypertrophic cardiomyopathy (HCM), yet many families lack a genetic diagnosis.
  • Next-generation sequencing (NGS) allows testing of candidate genes, necessitating family studies for variant interpretation.
  • Junctophilin-2 (JPH2) is a less-studied, non-sarcomeric candidate gene for cardiomyopathy.

Purpose of the Study:

  • To characterize the phenotype associated with a specific JPH2 gene variant (c.482C>A, p.(Thr161Lys)).
  • To review existing literature and databases regarding JPH2 variations and cardiac disease.
  • To investigate the role of the JPH2 p.(Thr161Lys) variant in Finnish hypertrophic cardiomyopathy families.

Main Methods:

  • Phenotypic characterization of nine Finnish index patients with HCM heterozygous for the JPH2 p.(Thr161Lys) variant.
  • Segregation studies within affected families.
  • Literature and database review of JPH2 variations in cardiac disease.

Main Results:

  • Identified 20 individuals with HCM across nine Finnish families carrying the JPH2 p.(Thr161Lys) variant.
  • Observed variant penetrance of 71% by age 60 and 100% by age 80.
  • Co-segregation of the variant with HCM phenotype in six families, presenting with left ventricular hypertrophy, arrhythmias, conduction abnormalities (including third-degree AV-block), and in some cases, end-stage heart failure.

Conclusions:

  • The heterozygous JPH2 p.(Thr161Lys) variant is proposed as a novel Finnish mutation responsible for atypical hypertrophic cardiomyopathy.
  • This finding expands the genetic landscape of HCM beyond sarcomeric genes.
  • The JPH2 variant is associated with a distinct clinical presentation including significant conduction defects.

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