Childhood glaucoma genes and phenotypes: Focus on FOXC1 mutations causing anterior segment dysgenesis and hearing...

Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.