Defining the clinical validity of genes reported to cause pulmonary arterial hypertension

ABSTRACT BACKGROUND Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The disease is caused by both genetic and environmental factors, with genetic variants in at least 27 genes displaying putative evidence for disease causality. Genetic testing is currently recommended for adults diagnosed with heritable or idiopathic PAH, and all children diagnosed with PAH. However, testing panels vary in the number and list of genes included, and exome/genome sequencing data may reveal variants in genes with varying levels of evidence for a relationship with PAH. METHODS An international panel of clinical and scientific experts in PAH was formed to perform an evidence-based review of heritable and idiopathic PAH gene-disease relationships. The panel performed literature searches and applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of PAH gene-disease relationships based on genetic and experimental evidence. RESULTS Of twenty-seven genes curated, twelve genes ( BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17 , and TBX4 ) were classified as having definitive evidence for causal effects of variants. Three genes, ABCC8, GGCX , and TET2 , were classified as having moderate evidence. Six genes ( AQP1, BMP10, FBLN2, KLF2, KLK1 , and PDGFD ) were classified as having limited evidence, and TOPBP1 was classified as having no known PAH relationship. Some of the recently identified genes with moderate or limited evidence may move to a higher classification as new evidence emerges. Five genes ( BMPR1A, BMPR1B, NOTCH3, SMAD1 , and SMAD4 ) were disputed due to a paucity of genetic evidence over time. CONCLUSIONS Evidence-based classification of PAH gene-disease relationships indicates that twelve genes have definitive evidence for causal effects of variants. We recommend that genetic testing panels include all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in testing panels. Clinical Perspective What is New? - Evidence-based PAH gene curation was performed using the NIH Clinical Genome Resource model. - Heritable and idiopathic PAH are caused by pathogenic variants in a diverse set of genes, including genes in the TGFβ/BMP pathway, channelopathy genes, cell metabolism genes, growth factors and transcription factors. - Four previously reported TGF-β/BMP pathway genes are disputed for a PAH gene-disease relationship. What Are the Clinical Implications? - All genes with definitive evidence for a PAH gene-disease relationship are strongly recommended to be included in genetic testing panels. - Caution should be taken in clinical interpretation for genes with less than definitive or strong evidence and disputed genes or genes with no known genetic evidence for PAH should not be included in genetic testing panels. - For undiagnosed cases, genetic reanalysis is recommended over time as new evidence for PAH gene-disease relationship is evaluated.