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Congenital glaucoma (CG) is a severe and inherited childhood optical neuropathy that leads to irreversible visual loss and blindness in children. CG pathogenesis remains largely unexplained in most patients. Herein we have extended our previous studies to evaluate the role of  FOXC2  and  PITX2  variants in CG. Variants of the proximal promoter and transcribed sequence of these two genes were analyzed by Sanger sequencing in a cohort of 133 CG families. To investigate possible oligogenic inheritance involving  FOXC2  or  PITX2  and  CYP1B1 , we also analyzed  FOXC2  and  PITX2  variants in a group of 25 CG cases who were known to carry  CYP1B1  glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare  FOXC2  variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare  PITX2  variants in the group of CG cases who were known to carry  CYP1B1  glaucoma-associated genotypes, and one of these  PITX2  variants arose  de novo . To the best of our knowledge, two of the identified variants ( FOXC2 : c.1183C>A, p.(H395N); and  PITX2 : c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent  PITX2  variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions ( FOXC2 : p.(C498R) and p.(H395N);  PITX2 : p.(P179T)). In summary, the increased frequency in PCG patients of rare  FOXC2  and  PITX2  variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.

Role of FOXC2 and PITX2 rare variants associated with mild functional alterations as modifier factors in congenital glaucoma