Identification of Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

Background: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition.

Methods And Results: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type -encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I synthase levels and urinary prostaglandin I metabolite levels. We identified another rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS.

Conclusions: In total, 2 rare nonsense/splice-site variants were identified in 2 pediatric patients with WS and severe PPS. variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.