Homozygous stop-gain variant in LRRC32, encoding a TGFβ receptor, associated with cleft palate, proliferative retinopathy, and developmental delay

  • Eur J Hum Genet. 2019 Aug;27(8):1315-1319. doi: 10.1038/s41431-019-0380-y.
Tamar Harel  1 ,  Ephrat Levy-Lahad  2 ,  Muhannad Daana  3 ,  Hadas Mechoulam  4 ,  Smadar Horowitz-Cederboim  2 ,  Michal Gur  5 ,  Vardiella Meiner  5 ,  Orly Elpeleg  5  6
Affiliations
  • 1. Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel. [email protected].
  • 2. Medical Genetics Institute, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
  • 3. Child Development Centers, Clalit and Maccabi Health Care Services, Jerusalem District, Jerusalem, Israel.
  • 4. Center for Pediatric Ophthalmology, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 5. Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • 6. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
PMID: 30976112 DOI: 10.1038/s41431-019-0380-y
Abstract

The transforming growth factor-beta (TGFβ) signaling pathway is essential for palatogenesis and retinal development. Glycoprotein A repetitions predominant (GARP), encoded by LRRC32, is a TGFβ cell surface receptor that has been studied primarily in the context of cellular immunity. We identified a homozygous stop-gain variant in LRRC32 (c.1630C>T; p.(Arg544Ter)) in two families with developmental delay, cleft palate, and proliferative retinopathy. Garp-null mice have palate defects and die within 24 h after birth. Our study establishes LRRC32 as a candidate disease-associated gene in humans and lends further support to the role of the TGFβ pathway in palatogenesis and retinal development.