From Genes to Disease: Reassessing LOXHD1 and AGBL1’s Contribution to Fuchs’ Dystrophy

Fuchs' endothelial corneal dystrophy (FECD) is a genetically complex eye disease associated with multiple genes. A recent systematic review has raised concerns about the causal role of variants in the <i>LOXHD1</i> and <i>AGBL1</i> genes in the development of FECD. Conflicting data have been reported on the expression of the <i>LOXHD1</i> and <i>AGBL1</i> genes in the corneal endothelium. Furthermore, only partial segregation of the variants was observed in familial cases. An analysis of published datasets was conducted to examine the expression of <i>LOXHD1</i> and <i>AGBL1</i> genes in normal and FECD-affected corneal endothelia and progenitor cells. Neither <i>LOXHD1</i> nor <i>AGBL1</i> genes were expressed in normal or FECD corneal endothelia or progenitor cells. In-house cohorts were screened for carriers of previously reported <i>LOXHD1</i> and <i>AGBL1</i> variants. Carriers and their first-degree relatives were invited for an ophthalmological examination to reassess the causal relationship of these variants with FECD phenotype. Three carriers of <i>LOXHD1</i> variants (one carrier of rs200242497 and two carriers of rs192376005) and two carriers of <i>AGBL1</i> variants (rs181958589 and rs185919705) were recruited. None of the carriers or first-degree relatives over 50 years exhibited phenotypic signs of FECD via ophthalmic examination. The causal role of the <i>AGBL1</i> and <i>LOXHD1</i> variants found in the carriers was not confirmed. Taken together, our findings do not support a causal role for <i>AGBL1</i> and <i>LOXHD1</i> in the development of FECD.