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.