Search

Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease. Instituto de Salud Carlos III (España) | Ref. FISPI18/01233 Xunta de Galicia | Ref. ED481A-2018/304

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.

Resumen Introduccion y objetivos La enfermedad venooclusiva pulmonar (EVOP) hereditaria se relaciona con mutaciones bialelicas en EIF2AK4 y se ha descrito una mutacion fundadora en pacientes ibericos de etnia gitana con EVOP familiar. Los objetivos son la caracterizacion fenotipica y el analisis de supervivencia de pacientes ibericos de etnia gitana con EVOP familiar portadores de la mutacion fundadora p.Pro1115Leu en EIF2AK4, segun su tolerancia clinica a vasodilatadores pulmonares (VDP). Estudio genetico familiar y analisis de factores socioculturales de la etnia con potencial impacto en la propagacion de la enfermedad. Metodos Estudio observacional de pacientes de etnia gitana con EVOP familiar incluidos en el Registro Espanol de Hipertension Arterial Pulmonar. Se realizo estudio genetico de EIF2AK4 a casos afectados y familiares (noviembre 2011-julio 2016) y estudio histopatologico pulmonar en caso de trasplante pulmonar o fallecimiento. Los pacientes se clasificaron en tolerantes y no tolerantes a VDP, comparando sus caracteristicas basales y la supervivencia libre de fallecimiento o el trasplante. Resultados Se estudio a 18 pacientes (9 casos indice y 9 familiares afectados). Se hallo la mutacion fundadora en homocigosis en EIF2AK4 en todos ellos y en 2 familiares sanos, y en heterocigosis en el 34,2% de familiares sanos. Se observo elevada consanguineidad, edad joven de reproduccion con multiparidad y pronostico sombrio de nuestra cohorte existiendo diferencias significativas entre pacientes tolerantes y no tolerantes. Conclusiones Se describen 2 fenotipos de EVOP hereditaria en etnia gitana segun tolerancia a VDP e histologia pulmonar, con impacto pronostico y distribucion familiar. Destacamos el papel de la consanguineidad en la propagacion de la enfermedad y una alta rentabilidad del cribado genetico familiar.