Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.MethodsTo identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene.ResultsWe identified SOX17 as a novel candidate risk gene (p = 5.5e−7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases.ConclusionsThese data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0566-x) contains supplementary material, which is available to authorized users.

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

“…GDF2 encodes a well-characterized ligand for BMPR2, and these data further confirm an important role for GDF2 in IPAH, as well as other PAH subclasses. Similar to the UK cohort, as well as our previous report of a cohort enriched in APAH-CHD cases 22 , we observed a low frequency of SOX17 variants (0.4%) in the PAH Biobank likely due, at least in part, to the paucity of APAH-CHD cases in both Biobank cohorts. Interestingly, a genome-wide association study of common SNPs involving both the PAH Biobank and the UK NIHR BioResource -Rare Diseases PAH Study identified SNPs in a putative endothelial-acting enhancer region of SOX17 in PAH 39 , suggesting that common variants may play an important role in susceptibility to PAH.…”

“…The data and resources are made available to the research community for hypothesis-driven projects via an application process (www.pahbiobank.org). A subset including 183 affected participants were included in previous publications from our group 14,20,22 . MLPA was performed with 100 ng of genomic DNA according to manufacturer's instructions using the P093 Salsa MLPA probe sets (MRC-Holland, Amsterdam, The Netherlands).…”

“…Rare mutations in SRY-related HMG-box transcription factor (SOX17), a key regulator of embryonic vasculogenesis, explain ~3.2% of APAH-CHD 22 , and 0.7% of IPAH 22,23 . The UK NIHR BioResource -Rare Diseases PAH Study, utilizing ~1000 PAH cases of primarily adultonset IPAH, identified an ATPase gene (ATP13A3), growth differentiation factor 2 (GDF2; also known as BMP9) and SOX17 as risk genes contributing to 0.8-1.1% of cases 23 .…”

The genetics of isolated congenital heart disease

“…Recent work has identified SOX17 as a contributor to CHD associated with pulmonary hypertension as well as isolated and familial pulmonary hypertension (Zhu et al, 2018). SOX17 is a transcriptional target of GATA4, and it inhibits signaling in the WNT/B-catenin pathway involved in cardiac development (Holtzinger, Rosenfeld, & Evans, 2010;Zorn et al, 1999).…”

Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease

“…Nevertheless, the presence of a mutation in the context of PAH-CHD could predispose for or accelerate progressive, thus irreversible disease. Mutations in BMPR2,48 49 and recently in the transcription factor Sox17,50 have been associated with PAH in CHD specifically. Whether this provides sufficient rationale to screen for these variants in the assessment of PAH reversibility remains to be determined.…”