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Lachlan Knight, Jonathan B Ruddle, Deepa A Taranath, Ivan Goldberg, James EH Smith, Glen Gole, Mark Y Chiang, Sean Mullany, James E Elder, Andrea L Vincent, Sandra Staffieri, David A Mackey, Susie Luu, Owen M Siggs, Emmanuelle Souzeau, Jamie E Craig; Childhood and Early-Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1515.
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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.
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.
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).
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.
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