Jul 22, 2018

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

Genome Medicine
Na ZhuWendy K Chung

Abstract

Pulmonary 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. To 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. We 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 varian...Continue Reading

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Mentioned in this Paper

Arterial Pulse Pressure
HMGB Proteins
Pulmonary Arterial Hypertension
Lung
Notch
Genes
Polycyclic Hydrocarbons, Aromatic
Virus Replication
Congenital Heart Disease
Congenital Disorders

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