Childhood and Early-Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry

Abstract

Purpose : Phenotypic and genotypic associations in childhood and early-onset glaucoma have not been well described in large datasets due to disease rarity, inconsistent use of disease definitions and limited availability of genetic testing. We performed a retrospective clinical and molecular study to report the relative frequencies of childhood and early-onset glaucoma subtypes and their genetic findings in a large single cohort.

Methods : We reviewed the referrals of individuals with childhood glaucoma (diagnosed 0 to <18 years) and early-onset glaucoma (diagnosed 18 to <40 years) recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) over a 13-year period (2007-2020). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classifications. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma.

Results : 290 individuals with childhood glaucoma and 370 individuals with early-onset glaucoma were referred to the ANZRAG. Primary glaucoma was most prevalent in both cohorts. In the childhood cohort, 57.6% of individuals (167/290) had primary congenital glaucoma and 19.3% (56/290) had juvenile open-angle glaucoma (JOAG). JOAG constituted 73.2% of the early-onset glaucoma cohort (271/370). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with non-acquired ocular anomalies (56.5%). Pathogenic variants in 18 genes associated with childhood and early-onset glaucoma were found. Biallelic variants in CYP1B1 (n=29; 5.7%) and heterozygous variants in MYOC (n=24; 4.7%) and FOXC1 (n=21; 4.2%) were most commonly reported amongst probands. Biallelic CYP1B1 variants were reported in twice as many females as males (66.7% vs. 33.3%; p=0.01).

Conclusions : We report on one of the largest international childhood and early-onset glaucoma cohorts using the CGRN classifications. Primary glaucomas were more prevalent than secondary glaucomas. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counselling. International collaborative efforts to characterise genetic associations in rare phenotypes will improve genetic diagnostic rates and management of childhood and early-onset glaucoma.

This is a 2021 ARVO Annual Meeting abstract.