Heterozygous GJA1 variants with ocular phenotype: Missense in domain but truncation out of domain

PURPOSE: Oculodentodigital dysplasia (ODDD) is a group disorder caused by GJA1 variants, of which glaucoma leading to blindness is a frequent complication of the ocular phenotype. In this study, the correlation of the GJA1 genotype with the ocular phenotype was analyzed systematically. METHODS: GJA1 variants were collected from in-house whole-exome sequencing data of 5,307 individuals. Potentially pathogenic variants (PPVs) were defined based on prediction of multiple in silico tools, related phenotypes, and previously established evidence. The characteristics of GJA1 PPVs were evaluated based on our data, gnomAD, and HGMD. RESULTS: In total, 21 rare variants in GJA1 were detected in 32 subjects from the study cohort. Four of the 21 variants were classified as PPVs, including two frameshift, one missense, and one in-frame deletion. The four PPVs were detected in four probands with microcornea or high hyperopia; two developed glaucoma. A systematic review of GJA1 variants in literature suggested that most heterozygous missense PPVs are located inside the connexin domain. All truncations downstream of the connexin domain are associated with autosomal dominant disease, while most truncations within the domain are associated with autosomal recessive ODDD. Ocular signs were present in 80.0% (116/145) of patients with GJA1 PPVs. Of the 116 patients, glaucoma was observed in 26.7% (31/116), among whom 77.4% (24/31) of cases occurred in patients ≥10 years old. CONCLUSIONS: Eye abnormalities are the most common signs associated with GJA1 PPVs, and they carry a high risk of developing glaucoma. The identification of GJA1 PPVs needs further attention and clarification.