Individuals heterozygous for LTBP2 loss-of-function variants have an increased risk of adult-onset primary open-angle glaucoma.

LTBP2

Heterozygosity for a loss-of-function variant in LTBP2, a recessive childhood glaucoma gene; extracellular matrix dysfunction in the trabecular meshwork and Schlemm's canal

Using exome data from more than 450,000 UK Biobank participants, this study tested whether heterozygosity for loss-of-function (LoF) variants in three autosomal recessive childhood glaucoma genes (LTBP2, CYP1B1, CPAMD8) is associated with adult-onset primary open-angle glaucoma. Gene burden testing showed increased risk in heterozygous LTBP2 LoF carriers (OR 4.14; 95% CI 2.73-6.28; p = 4.0 × 10⁻¹³), an association replicated in the All of Us cohort. Glaucoma participants carrying an LTBP2 LoF variant were diagnosed 8 years earlier than non-carriers. No significant association was found for CYP1B1 or CPAMD8, and single-nucleus expression of LTBP2 points to extracellular matrix dysfunction in the trabecular meshwork and Schlemm's canal.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This finding changes the status of an LTBP2 loss-of-function heterozygote found on exome/genome: no longer a mere healthy carrier, but a person at increased risk of adult glaucoma, which raises the question of ophthalmological surveillance in relatives of recessive cases. A biobank-derived OR of 4 still needs to be translated into absolute risk before any recommendation. The negative result for CYP1B1 is just as informative for genetic counselling.

Analysis by Dr Thibaut Benquey