Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

Cardiovascular Research
Adrien GeorgesNabila Bouatia-Naji

Abstract

Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on huma...Continue Reading

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Jan 10, 2019·Journal of the American College of Cardiology·David AdlamNabila Bouatia-Naji
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Citations

Dec 10, 2020·The New England Journal of Medicine·Esther S H Kim
Jan 5, 2021·Cardiovascular Research·Alexandre PersuBart Loeys
Mar 20, 2021·Cardiovascular Research·Alexandre PersuAndrzej Januszewicz
Jun 11, 2021·Circulation Research·Esther S H KimSanthi K Ganesh
Oct 29, 2021·Circulation. Genomic and Precision Medicine·Asma Amrani-MidounNabila Bouatia-Naji

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