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Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2018;71:86-94 - Vol. 71 Num.02 DOI: 10.1016/j.rec.2017.03.034

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

Paula Navas Tejedor a, Julián Palomino Doza b,c, Jair Antonio Tenorio Castaño d,e, Ana Belén Enguita Valls f, José Julián Rodríguez Reguero g, Amaya Martínez Meñaca h, Ignacio Hernández González c,i, Héctor Bueno Zamora c,j,k, Pablo Daniel Lapunzina Badía d,e, Pilar Escribano Subías c,i,j,

a Servicio de Cardiología, Hospital Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
b Unidad de Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
c Servicio de Cardiología, Hospital Universitario 12 de Octubre, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
d Instituto de Genética Médica y Molecular (INGEMM), Instituto de Investigación La Paz (IdiPAZ), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain
e Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
f Servicio de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, Spain
g Servicio de Cardiología, Hospital Central de Asturias, Oviedo, Asturias, Spain
h Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
i Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
j Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
k Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Keywords

Hereditary pulmonary veno-occlusive disease. Pulmonary arterial hypertension. EIF2AK4. Pulmonary vasodilators. Romani ethnicity.

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.

Article

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1885-5857/© 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

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