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Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies.We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion.We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n = 142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata.In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.

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.