Genetic background in pediatric pulmonary arterial hypertension. Should we change the current recommendations for genetic testing?
Authors: Cruz Utrilla A , Gallego N , Torrent A , Garrido-Lestache E , Guillen I , Arias S , Moya A , Mendoza A , Espin J , Rodriguez Vazquez M M , Playan-Escribano J , Labrandero C , Tenorio Castano J A , Escribano Subias P , Del Cerro M J 
Published: October 2021

Abstract

Background
Pulmonary arterial hypertension (PAH) is a rare and severe disease, genetically predisposed in a high proportion of patients. PAH is subclassified in different subtypes depending on the underlying condition. Gene variants are more frequent among heritable or idiopathic forms. Nevertheless, pathogenic variants have been described across the entire spectrum of this disease. Evidence regarding genetics in pediatric PAH is scarce [1].

Purpose
Our aim is to describe the prevalence of significant gene mutations among a pediatric PAH cohort and to define specific data in the different subtypes.

Methods
Samples for genetic studies were obtained from blood tests of patients included in the Spanish National Registry of Pediatric Pulmonary Hypertension (REHIPED). Guardians signed informed consent before the inclusion in the study. Qualitative variables were compared by Chi-square test. Quantitative variables were assessed by Kruskal-Wallis, considering the asymmetric distribution of variables. STATA 14.0 was used for analyses.

Results
Sixty four patients were included between 2011 and 2021. Median age of the entire sample was 7.1 years (2.0–12.6) and 42.2% of them were male. There were significant differences in the age at diagnosis and race between the different included groups (table). Pathogenic or likely pathogenic variants were more frequent in familial pulmonary venooclusive disease (PVOD) and familial PAH cases. A similar percentage of mutations were found in idiopathic cases and in PAH associated with congenital heart disease (Figure). Gene variants in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) were the most frequent mutations in the PAH familial cohort and there was also the most frequent finding in congenital heart disease and sporadic PAH, in conjunction with the TBX4 gene. Homozygous or compound heterozygous EIF2AK4 (eukaryotic translation initiation factor 2 a kinase 4) mutations were found in all the patients diagnosed with PVOD. Heritable PAH and PVOD cases were diagnosed more frequently after family screening.

Conclusions
This study shows a comparable proportion of pathogenic-likely pathogenic gene mutations in patients diagnosed of pulmonary arterial hypertension associated with congenital heart disease and idiopathic cases, with similar distribution of specific genes. BMPR2 and TBX 4 were the most frequent gene variants in this pediatric PAH population. BMPR2 and EIF2AK4 are the most common mutations in familial PAH and PVOD subtypes, respectively.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ACU holds a Rio Hortega Grant from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.JAT and NG hold grants from FEDER (Federaciόn Española de Enfermedades Raras) and from the FCHP. Table 1. Characteristics of PAH subtypesFigure 1. PAH and ACMG classification.