Variable Expressivity of a Founder Mutation in the EIF2AK4 Gene in Hereditary Pulmonary Veno-occlusive Disease and Its Impact on Survival

Rev Esp Cardiol (Engl Ed). 2018 Feb;71(2):86-94. doi: 10.1016/j.rec.2017.03.034. Epub 2017 Jul 9.
[Article in English, Spanish]

Abstract

Introduction and objectives: Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course.

Methods: Observational study of Romani patients with familial PVOD included in the Spanish Registry of Pulmonary Arterial Hypertension. Genetic screening of EIF2AK4 was performed in index cases and relatives between November 2011 and July 2016 and histological pulmonary examination was carried out in patients who received a lung transplant or died. The patients were divided into 2 groups depending on their tolerance to PVD, with comparison of baseline characteristics and survival free of death or lung transplant.

Results: Eighteen Romani patients were included: 9 index cases and 9 relatives. The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD.

Conclusions: We describe 2 phenotypes of hereditary PVOD depending on tolerance to PVD, with prognostic impact and familial distribution. Consanguinity may have a negative impact on the transmission of PVOD, with familial genetic screening showing high effectiveness.

Keywords: EIF2AK4; Enfermedad venooclusiva pulmonar familiar; Etnia gitana; Hereditary pulmonary veno-occlusive disease; Hipertensión arterial pulmonar; Pulmonary arterial hypertension; Pulmonary vasodilators; Romani ethnicity; Vasodilatadores pulmonares.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Adult
  • DNA / genetics*
  • DNA Mutational Analysis
  • Female
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Pulmonary Veno-Occlusive Disease / congenital
  • Pulmonary Veno-Occlusive Disease / genetics*
  • Pulmonary Veno-Occlusive Disease / mortality
  • Spain / epidemiology
  • Survival Rate / trends
  • Young Adult

Substances

  • DNA
  • EIF2AK4 protein, human
  • Protein Serine-Threonine Kinases