Identification of OPTN p.(Asn51Thr): A novel pathogenic variant in primary open-angle glaucoma

Pathogenic variants in TBK1, MYOC, and OPTN are associated with primary open-angle glaucoma (POAG) with severe visual field defects. This study aims to understand further POAG-related pathogenic variant(s) based on a cohort of East Asian populations that have not been well-characterized.

We conducted a comprehensive screening of TBK1, MYOC, and OPTN variants in 174 POAG Japanese patients, followed by 8380 population-specific genome sequencing data references, segregation analysis, and functional protein assays to determine pathogenic variants.

Despite the small sample size, 4 variants were novel, 2 of which p.(Cys5Trp) and p.(Thr293Met) were in the MYOC gene, and 2 p.(Asn51Thr), and p.(Gln142His) were in the OPTN. Notably, the OPTN p.(Asn51Thr) missense variant adjacent to the p.(Glu50Lys) variant, a well-known POAG pathogenic variant, was segregated from all proband's family members with POAG. Moreover, in silico and in vitro analyses revealed that the OPTN p.(Asn51Thr) protein increased binding instability, interactions of the OPTN-TBK1 complex, and enhanced protein insolubility, likewise the p.(Glu50Lys) protein.

Our findings may provide further genetic insights into rare variants of POAG and support the clear conclusion that OPTN p.(Asn51Thr) is a novel likely pathogenic variant.