Genetic background of pediatric PAH in Spain and its clinical implications: data from the REHIPED Spanish Registry

Abstract

Background The genetic background of pulmonary arterial hypertension (PAH) in the Spanish pediatric population could be different from the genetic background described in other countries. Besides, clinical implications of a positive genetic result in the PAH pediatric population are not fully understood yet, and could result in the “reclassification” of patients from one PAH group to another type among the current pediatric classification. Material and methods Patients under 19 years at diagnosis included in the REHIPED registry from January 2011 to December 2021 were included. Clinical variables and genetical results were recorded. Succesive NGS panels involving up to 35 genes were used. After the results of the genetic testing, we analyzed differences in survival, and if patients “moved” to another category in the current Nice classification. Results In the selected cohort of 98 patients (56.1% female), median age at diagnosis was 7.1 years (IQr 1.5–14.7), and ethnicity as follows: Caucasian (81.6%), Romani (8.2%), others (10.2%) (Table 1). Before the genetic testing, patients had been classified as Idiopathic (53.1%), Congenital Heart Disease-PAH (30.6%), Heritable (5.1%), Pulmonary veno-oclusive disease (PVOD) 6.1%, and Multisystemic disorder associated with PAH (5.1%). Pathogenic or likely pathogenic variants were found in 44 of the screened patients (44.9%): BMPR2 (12 cases), EIF2AK4 (9), TBX4 (n=4), MECP2 (n=3), KCNK3 (n=2), FOXF1 (n=2), NFU1 (N=4), ACVRL1 (n=1), BMPR1B (n=1), CLBCI (n=1), GBE1 (n=1), GDF2 (n=1), SOX17 (n=1), VHL (n=1), and digenic pathogenic variant in ABCC8/SMAD1 (n=1). After genetic analysis, 28 patients (28.6%) were “reclassified” (Fig. 1, panel A), with HPAH, PVOD and multisystemic disorders increasing up to 18.4%, 8.2%, and 12.2%, respectively. Worse Survival from death or lung transplantation was observed in heritable PVOD and multisystemic disorders (Fig. 1, panel B). Conclusions The Spanish pediatric PAH population showed higher prevalence of EIF2AK4 than other pediatric registries. Genetic testing resulted in the “reclassification” of a significant number of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rio Hortega grant from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III).