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

PURPOSE

Pathogenic variants in , , and 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.

METHODS

We conducted a comprehensive screening of , , and 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.

RESULTS

Despite the small sample size, 4 variants were novel, 2 of which p.(Cys5Trp) and p.(Thr293Met) were in the gene, and 2 p.(Asn51Thr), and p.(Gln142His) were in the . Notably, the 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 p.(Asn51Thr) protein increased binding instability, interactions of the OPTN-TBK1 complex, and enhanced protein insolubility, likewise the p.(Glu50Lys) protein.

CONCLUSION

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