Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

Background: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. Objectives: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. Methods: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan–Meier curves. Results: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease—PVOD—in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders—MSD—in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was “reclassified”, with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. Conclusions: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

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).

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