TY - JOUR
T1 - 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
AU - Hexner-Erlichman, Zufit
AU - Fichtman, Boris
AU - Zehavi, Yoav
AU - Khayat, Morad
AU - Jabaly-Habib, Haneen
AU - Izhaki-Tavor, Lee S.
AU - Dessau, Moshe
AU - Elpeleg, Orly
AU - Spiegel, Ronen
N1 - Publisher Copyright:
Copyright © 2022 Hexner-Erlichman, Fichtman, Zehavi, Khayat, Jabaly-Habib, Izhaki-Tavor, Dessau, Elpeleg and Spiegel.
PY - 2022/5/17
Y1 - 2022/5/17
N2 - 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.
AB - 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.
KW - GARP protein
KW - LRRC32 gene
KW - TGF-β
KW - cleft palate
KW - retinopathy
UR - http://www.scopus.com/inward/record.url?scp=85131605214&partnerID=8YFLogxK
U2 - 10.3389/fped.2022.859034
DO - 10.3389/fped.2022.859034
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C2 - 35656379
AN - SCOPUS:85131605214
SN - 2296-2360
VL - 10
JO - Frontiers in Pediatrics
JF - Frontiers in Pediatrics
M1 - 859034
ER -