LAUSR

PURPOSE To report the relative frequencies of childhood and early-onset glaucoma subtypes and their genetic findings, in a large single cohort. DESIGN Retrospective clinical and molecular study. PARTICIPANTS All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early-onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. METHODS We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. MAIN OUTCOME MEASURES The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. RESULTS 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early-onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG) and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma (JOAG). JOAG constituted 73.2% of the early-onset glaucoma cohort (271/370, 513 eyes). 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%). 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 with PCG (66.7% vs 33.3%, p=0.02). CONCLUSIONS We report on the largest cohort of individuals with childhood and early-onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counselling. International collaborative efforts are required to identify further genes as the majority of cases still lack a clear molecular diagnosis.