Abstract
Purpose :
Glaucoma is one of the most heritable human diseases, with variants at the TMCO1 locus among the strongest common genetic risk factors known. This risk has recently been attributed to expansion of an intronic 28bp variable number tandem repeat (VNTR) in TMCO1. We sought to understand the clinical impact of TMCO1 VNTR expansion length in a glaucoma registry.
Methods :
3123 participants were genotyped at two variants associated with TMCO1 VNTR expansions of increasing lengths. In a subset of individuals, repeat lengths were also measured by a targeted PCR-based assay, by short-read whole genome sequencing, or by nanopore long-read sequencing. VNTR lengths were then associated with a range of clinical outcomes.
Results :
Increased TMCO1 VNTR length was associated in a dose-dependent manner with a younger age at glaucoma diagnosis, higher prevalence of high-tension glaucoma, higher IOP, and a higher likelihood of glaucoma family history. The clinical phenotype of individuals with the longest TMCO1 repeat expansions was similar to that of MYOC p.Gln368Ter heterozygotes, although at a 3.5 times higher frequency in the general population.
Conclusions :
TMCO1 VNTR expansions represent a new class of genetic risk variant in glaucoma, with longer expansions associated with earlier-onset and more severe disease. The molecular mechanism by which these expansions increase glaucoma risk remains to be determined.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.