A Novel Homozygous Missense Variant in the LRRC32 Gene Is Associated With a New Syndrome of Cleft Palate, Progressive Vitreoretinopathy, Growth Retardation, and Developmental Delay

Zufit Hexner-Erlichman, Boris Fichtman, Yoav Zehavi, Morad Khayat, Haneen Jabaly-Habib, Lee S. Izhaki-Tavor, Moshe Dessau, Orly Elpeleg, Ronen Spiegel

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1 Scopus citations

Abstract

Cleft lip and/or cleft palate are a common group of birth defects that further classify into syndromic and non-syndromic forms. The syndromic forms are usually accompanied by additional physical or cognitive abnormalities. Isolated cleft palate syndromes are less common; however, they are associated with a variety of congenital malformations and generally have an underlying genetic etiology. A single report in 2019 described a novel syndrome in three individuals, characterized by cleft palate, developmental delay and proliferative retinopathy due to a homozygous non-sense mutation in the LRRC32 gene encoding glycoprotein A repetitions predominant (GARP), a cell surface polypeptide crucial for the processing and maturation of transforming growth factor β (TGF-β). We describe a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy. Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene, which resulted in substitution of a highly conserved isoleucine to threonine. Protein modeling suggested this variant may negatively affect GARP function on latent TGF-β activation. In summary, our report further expands the clinical features of cleft palate, proliferative retinopathy and developmental delay syndrome and emphasizes the association of LRRC32 pathogenic variants with this new syndrome.

Original languageEnglish
Article number859034
JournalFrontiers in Pediatrics
Volume10
DOIs
StatePublished - 17 May 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Hexner-Erlichman, Fichtman, Zehavi, Khayat, Jabaly-Habib, Izhaki-Tavor, Dessau, Elpeleg and Spiegel.

Keywords

  • GARP protein
  • LRRC32 gene
  • TGF-β
  • cleft palate
  • retinopathy

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