Abstract
Purpose :
Primary congenital glaucoma (PCG) is a rare inherited eye disorder that is associated with a significant proportion of childhood blindness. Understanding its genetic heterogeneity is crucial for improving diagnosis, prognosis, and clinical management. Our study investigated 70 PCG cases from 64 unrelated families, who were recruited into the Genomics England 100,000 Genomes Project (GE100KGP) for whole genome sequencing (WGS), to ascertain molecular diagnostic yield.
Methods :
The sequencing data of unsolved patients with primary diagnoses of primary congenital glaucoma (HP:0008007), developmental glaucoma (HP:0001087), late-onset congenital glaucoma (HP:0008041), or buphthalmos (HP:0000557) were retrieved. Variants in 40 known genes associated with glaucoma were filtered for this analysis. Single nucleotide variants (SNVs) were prioritized based on minor allele frequency, impact, consequence type, mode of inheritance, location within the gene, and deleteriousness. Structural variants (SVs) were prioritized based on duplications or deletions that overlapped exonic regions of genes, with ACMG scores of 3 or higher. An interdisciplinary team evaluated the genetic findings to validate variant deleteriousness.
Results :
A genetic diagnosis was found in 11 PCG patients from 10 unrelated families, resulting in a 31% molecular diagnostic rate. We found that 55% of the solved cases had non-syndromic PCG, while 45% had syndromic PCG, displaying various systemic anomalies. Moreover, 64% had simplex PCG, while 36% had complex PCG with additional ocular phenotypes. Our study identified 12 potentially disease-causing variants in 7 unique genes, including CYP1B1, SLC4A11, TEK, ADAMTS17, FOXC1, MYOC, and SBF2. Of these, 3 novel pathogenic and likely pathogenic SNVs were in SBF2 and TEK genes, and 2 novel copy number variants were in ADAMTS17 and FOXC1.
Conclusions :
Our study provides the largest comprehensive characterization of the genetic and phenotypic spectrum of PCG in 70 patients recruited through the GE100KGP. Most PCG cases, 69% in our cohort, are still genetically unsolved likely due to complex causative factors such as gene modifiers, non-coding variants, or non-Mendelian etiologies. Combining high-throughput sequencing technologies with regular re-analysis of genomic data could resolve these limitations and may potentially help with personalized glaucoma treatments in the future.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.