SOX17 – Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy featuring pulmonary vascular remodeling, increased pulmonary arterial pressure, and eventual right heart failure ([PMID:30029678]). Pathogenic variants in several genes underlie heritable and idiopathic PAH, with SOX17 emerging as a definitive risk gene for both PAH with congenital heart disease (PAH-CHD) and idiopathic/familial PAH. Genetic sequencing studies have identified rare deleterious coding variants in SOX17 in 3.2% of PAH-CHD cases (256 probands) and in ~0.7% of PAH without CHD ([PMID:30029678]), with overall >67 probands described to date ([PMID:37895315]).

SOX17-related PAH demonstrates autosomal dominant inheritance with haploinsufficiency as a primary mechanism. Loss-of-function (LoF) and damaging missense variants cluster in the HMG-box and C-terminal regions, including the recurrent c.379C>T (p.Glu185Ter) variant observed co-segregating with PAH in a multisibling family ([PMID:33952808]). Variant spectrum now comprises >20 unique alleles, including frameshifts, nonsense, canonical splice, and missense changes, often de novo in pediatric-onset cases ([PMID:29650961]).

Familial segregation is documented in at least three kindreds, with LoF variants co-segregating with disease affection status across multiple generations ([PMID:33952808]; [PMID:29650961]). Penetrance is high, with affected relatives exhibiting early-onset severe PAH, frequently complicated by intracardiac shunts when associated with CHD ([PMID:35618278]).

Functional studies support a haploinsufficiency mechanism: patient-derived and engineered SOX17 LoF alleles fail to activate transcription of key vascular targets (e.g., NOTCH1) and cannot restrain ß-catenin signaling, recapitulating endothelial dysfunction ([PMID:33952808]; [PMID:29650961]). Endothelial-specific Sox17 knockout mice develop spontaneous and hypoxia-exacerbated pulmonary hypertension, demonstrating increased proliferation, apoptosis resistance, and barrier impairment via E2F1-mediated pathways ([PMID:37737027]). Moreover, common and rare enhancer variants upstream of SOX17 reduce endothelial expression, altering transcription factor binding and further predisposing to PAH in vivo ([PMID:37066790]).

No studies have convincingly refuted the SOX17–PAH association; rather, extensive concordant genetic and experimental data across independent cohorts and model systems reinforce causality. Additional large-scale sequencing continues to expand the variant spectrum but does not alter the autosomal dominant, haploinsufficiency paradigm.

SOX17 testing is clinically actionable: identifying pathogenic variants informs prognosis, guides early referral for interventional shunting in refractory infants, and enables family counseling.

Key Take-home: Germline SOX17 variants cause a definitive autosomal dominant PAH syndrome through haploinsufficiency, and should be included in diagnostic panels to enable precision management of affected families.

References

• Genome Medicine | 2018 | Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. PMID:30029678
• Nature Communications | 2018 | Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. PMID:29650961
• International Heart Journal | 2021 | SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension. PMID:33952808
• The European Respiratory Journal | 2022 | An emerging phenotype of pulmonary arterial hypertension patients carrying SOX17 variants. PMID:35618278
• Genes | 2023 | Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature. PMID:37895315
• Circulation | 2023 | SOX17 Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension. PMID:37066790
• Hypertension | 2023 | E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension. PMID:37737027

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