Purpose: To describe a novel association of TGFBI variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome as well as among unrelated cases of Juvenile onset open angle glaucoma (JOAG) along with the mechanistic impact of the variants on the protein. Methods: This study of one family of GAPO with congenital glaucoma and three unrelated patients of JOAG analysed a common link to glaucoma pathogenesis. We report ocular features of 3 girls with GAPO syndrome born of consanguineous marriage in a multi- generation consanguineous family. The proband (a 4year old girl) and her younger sibling (1year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10year old female) had features of GAPO syndrome without glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all three affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense variant in the TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We further found three other unrelated patients with JOAG with no known glaucoma causing gene mutations but having three different missense variants in the TGFBI gene. One of these JOAG patients had familial granular corneal dystrophy. Molecular dynamic simulations of the TGFBI and 3-D structural models of three of its variants showed significant alterations, which could influence TGFBI function. Conclusions: Variations in the TGFBI gene could have a possible role in the pathogenesis of congenital and Juvenile onset open angle glaucomas that needs further evaluation.
