Pathogenic variants of genes associated with pulmonary arterial hypertension (PAH): Insights from Trans-Omics for Precision Medicine (TOPMed) study participants

<bold>Background:</bold> Given the rarity of PAH, a critical gap exists in understanding the distribution and impact of its associated genetic variants across large cohorts. We sought to examine the frequency and characteristics of rare variants within established PAH genes in study cohorts not specifically enriched with patients with PAH. <bold>Methods:</bold> We used the BRAVO variant browser to display chromosome locations, alleles, functional annotations and allele frequencies for 868 million variants observed in 150899 whole genomes from 20 ancestries in TOPMed freeze 10. We filtered variants in 12 PAH genes based on quality control measures, retaining only loss-of-function single nucleotide variants and insertions/deletions. We assessed the pathogenicity of the variants using ClinVar. <bold>Results:</bold> We found a total of 248 loss-of-function variants (202 high-confidence; 132 SNVs; 116 indels) from the analyzed genes in 150899 subjects. Only 60 variants were reported in ClinVar. With the exception of a benign variant in CAV1, all variants were found to be heterozygous. We identified pathogenic variants in 9 out of the 12 genes in 111 subjects. While only 3 subjects harbored a pathogenic BMPR2 variant, 70 subjects carried a pathogenic variant in the EIF2AK4 gene. We additionally detected pathogenic variants in ACVRL1 (10 subjects), ATP13A3 (2 subjects), CAV1 (3 subjects), ENG (6 subjects), SMAD9 (12 subjects), SOX17 (1 subject), and TBX4 (4 subjects). <bold>Conclusion:</bold> Loss-of-function variants in PAH genes are rare but can be detected in a diverse population sample. Future work will attempt to ascertain clinical phenotypes in available study participants.