Exome-wide screening discovers novel pathogenic variants in Vietnamese primary congenital glaucoma patients

Primary congenital glaucoma (PCG), the most prevalent pediatric variant, is a major contributor of childhood blindness globally. Traditional diagnosis relies on clinical features such as the classic triad (epiphora, photophobia, and blepharospasm), elevated intraocular pressure (IOP), corneal enlargement and optic disc cupping. Early diagnosis remains challenging as the conventional diagnosis often requires cooperation from pediatric patients.

To identify the genetic etiology and underlying variants in a cohort of Vietnamese patients diagnosed with PCG using WES.

A cohort of 32 Vietnamese patients with clinically diagnosed PCG was subjected to Whole-Exome Sequencing (WES) for genetic etiology identification. Validation of candidate variants was achieved using Sanger sequencing, with pathogenicity classification following ACMG/AMP guideline.

Genetic examination revealed pathogenic/likely pathogenic variants in 18.75% of the cohort (6/32 probands), involving in three genes: CYP1B1, TEK, FOXC1; and VUS in 6.25% (2/32 probands) spanning the gene LTBP2, FBN1. Three novel point variants in glaucoma-assiciated genes were identified, including a frameshift in FOXC1 (p.Tyr5fs*40), a stop-gained variant in TEK (p.Trp216*), and a missense variant in FBN1 (p.Lys54Glu). Additionally, a new putative large chromosomal deletion was identified on FOXC1 gene. While CYP1B1 remains a primary driver of PCG, finding alterations in FOXC1 and FBN1-typically associated with Axenfeld-Rieger and Marfan syndromes-underscores the clinical overlap between PCG and other developmental or systemic disorders.

Achieving a 25% diagnostic rate, the study suggests that broader genetic testing by WES would greatly beneficial in the identification and categorization of glaucoma. The data suggest that WES is a powerful diagnostic resource, particularly when corneal clouding impedes fundus examination, and can provide essential insights into systemic syndromic risks.