Abstract
Childhood glaucoma is a heterogeneous disease and can be associated with various genetic alterations. The aim of this study was to report first results of the phenotype–genotype relationship in a German childhood glaucoma cohort. Forty-nine eyes of 29 children diagnosed with childhood glaucoma were prospectively included in the registry. Besides medical history, non-genetic risk factor anamnesis and examination results, genetic examination report was obtained (23 cases). DNA from peripheral blood or buccal swab was used for molecular genetic analysis using a specific glaucoma gene panel. Primary endpoint was the distribution of causative genetic mutations and associated disorders. Median age was 1.8 (IQR 0.6; 3.8) years, 64% participants were female. Secondary childhood glaucoma (55%) was more common than primary childhood glaucoma (41%). In 14%, parental consanguinity was indicated. A mutation was found in all these cases, which makes consanguinity an important risk factor for genetic causes in childhood glaucoma. CYP1B1 (30%) and TEK (10%) mutations were found in primary childhood glaucoma patients. In secondary childhood glaucoma cases, alterations in CYP1B1 (25%), SOX11 (13%), FOXC1 (13%), GJA8 (13%) and LTBP2 (13%) were detected. Congenital cataract was associated with variants in FYCO1 and CRYBB3 (25% each), and one case of primary megalocornea with a CHRDL1 aberration. Novel variants of causative genetic mutations were found. Distribution of childhood glaucoma types and causative genes was comparable to previous investigated cohorts. This is the first prospective study using standardized forms to determine phenotypes and non-genetic factors in childhood glaucoma with the aim to evaluate their association with genotypes in childhood glaucoma.
Highlights
Several cohorts investigated the impact of mutations in single genes on clinical parameters or success of surgery, but merely included distinct mutations such as CYP1B1, MYOC or LTBP2 in primary congenital glaucoma (PCG) [27,28,29,30,31,32,33,34,35,36,37,38,39] or focused on individual syndromes possibly leading to secondary childhood glaucoma such as Axenfeld–Rieger anomaly [11,40] or Aniridia [41]
In all cases associated with parental consanguinity, we found a causative genetic mutation
We recently reported a case of SOX11-related Coffin–Siris syndrome with the first observation of childhood glaucoma [17] presenting with maximal intraocular pressure of 43 mmHg, microcornea with central opacity, aniridia and cataract
Summary
Previous reports from western countries found incidences of primary congenital glaucoma (PCG) ranging from 1:10,000 to 1:40,000 births [2,3] whereas it is higher in countries where consanguine marriage is more common. The incidence was reported 1:2500 [4], and the highest incidence of 1:1250 was found in a cohort of Slovakian Romani people [5]. This indicates the high impact of inheritance in childhood glaucoma. The most frequently mutated gene in PCG is CYP1B1, which is located on chromosome 2p22-p21 (locus GLC3A).
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