Purpose: Our aim was to identify the clinical features and outcomes of PAH patients with RNF213 p.Arg4810Lys variant.
Methods: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. Hemodynamics and prognosis were evaluated in the patients with RNF213 p.Arg4810Lys variant and the patients with bone morphogenic protein receptor type 2 (BMPR2) mutations.
Results: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those in BMPR2 mutation carriers (n=36) (comparison of changes in mean pulmonary arterial pressure, P=0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs. 93%, P<0.001) (Figure).
Conclusions: PAH patients with the RNF213 p.Arg4810Lys variant were associated with a poor reactivity to vasodilator drugs and poor clinical outcomes even in the recent era. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.