Association of Variants in TMEM45A With Keratoglobus.

Importance Keratoglobus is a rare corneal disorder characterized by generalized thinning and globular protrusion of the cornea. Affected individuals typically have significantly decreased vision and are at risk of corneal perforation. The genetic basis and inheritance pattern of isolated congenital keratoglobus are currently unknown. Objective To identify the genetic basis of isolated congenital keratoglobus. Design, Setting, and Participants This case series and molecular analysis studied 3 unrelated nonconsanguineous families with keratoglobus at a medical center in Israel. Data were collected from June 2019 to March 2021 and analyzed during the same period. Exposures Whole-exome sequencing and direct Sanger sequencing, expression analysis by real-time polymerase chain reaction, splice-site variant analysis, immunohistochemical staining, and histological evaluation of a knockout mouse model. Main Outcomes and Measure Molecular characteristics associated with keratoglobus. Results Four pediatric patients (3 male individuals) from 3 families had clinical findings consistent with keratoglobus. These included globular protrusion, corneal thinning more prominent at the periphery, and high astigmatism. Truncating and splice site variants were identified in theTMEM45Agene, which fully segregate with the disorder. All affected individuals were homozygous or compound heterozygous for variants in theTMEM45Agene, while unaffected family members were heterozygous carriers. Expression analysis in healthy controls showed thatTMEM45Awas expressed 23 times higher in the human cornea compared with peripheral blood. Immunohistochemical staining of the TMEM45A protein in normal corneas confirmed its expression in the corneal stroma and epithelium. ATMEM45Aknockout mouse model showed structural features consistent with keratoglobus. Conclusions and Relevance Expression ofTMEM45Ahas been previously shown to result in upregulation of extracellular matrix components and fibrosis. These results suggest that isolated congenital keratoglobus is an autosomal recessively inherited disorder associated with variants in theTMEM45Agene.