Exome data clouds the pathogenicity of genetic variants in Pulmonary Arterial Hypertension.

Yeganeh Abbasi,Jacob Tfelt-Hansen,Edda Spiekerkoetter,Charlotte Glinge,Seyed Bahador Izadyar,Roham T Zamanian,Reza Jabbari,Javad Jabbari,Jørn Carlsen

doi:10.1002/mgg3.452

Abstract

BackgroundWe aimed to provide a set of previously reported PAH‐associated missense and nonsense variants, and evaluate the pathogenicity of those variants.MethodsThe Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH‐associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH‐associated missense and nonsense variants. The pathogenicity of previously reported PAH‐associated missense variants evaluated by using four in silico prediction tools.ResultsIn total, 14 PAH‐associated genes and 180 missense and nonsense variants were gathered. The BMPR2, the most frequent reported gene, encompasses 135 of 180 missense and nonsense variants. The exome sequencing project comprised 9, and the exome aggregation consortium counted 25 of 180 PAH‐associated missense and nonsense variants. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis.ConclusionThis is the first evaluation of previously reported PAH‐associated missense and nonsense variants. The BMPR2 identified as the major gene out of 14 PAH‐associated genes. Based on findings, the ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH.

Highlights

Pulmonary arterial hypertension (PAH) is a rare, progressive, and deathly disease (Hoeper et al, 2014; Machado, 2012; Simonneau et al, 2013)
Background: We aimed to provide a set of previously reported PAH‐associated missense and nonsense variants, and evaluate the pathogenicity of those variants
The topoisomerase 2‐binding protein 1 (TOPBP1) and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a rare, progressive, and deathly disease (Hoeper et al, 2014; Machado, 2012; Simonneau et al, 2013). PAH is subclassified into four groups: idiopathic PAH, heritable PAH, drug, and toxin induced, and lastly associated with certain other diseases Methods: The Human Gene Mutation Database, PubMed, and Google Scholar were searched for previously reported PAH‐associated genes and variants. Thereafter, both exome sequencing project and exome aggregation consortium as background population searched for previously reported PAH‐associated missense and nonsense variants. The pathogenicity of previously reported PAH‐associated missense variants evaluated by using four in silico prediction tools. The TOPBP1 and ENG genes are unlikely to be the monogenic cause of PAH pathogenesis based on allele frequency in background population and prediction analysis. Conclusion: This is the first evaluation of previously reported PAH‐associated missense and nonsense variants. The ENG and TOPBP1 gene are not likely to be the monogenic cause of PAH

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