Description
Developmental glaucoma is a potentially blinding condition caused by raised intraocular pressure in babies and young children. It may be isolated or syndromic and is known to have a genetic basis, but in the UK the molecular diagnostic rate is less than 25%. Established causes of developmental glaucoma include pathogenic variants in CYP1B1, FOXC1, PAX6 and SLC4A11.
The 100,000 Genomes Project is a national study of families with rare diseases and cancer who underwent whole genome sequencing to aid research into the genetic basis of these conditions. This includes 98 families with developmental glaucoma, of whom 67 remain without a molecular diagnosis. Recruitment finished in 2018, and since then 44 additional genes have been associated with developmental glaucoma in the published literature.
We re-evaluated the whole genome sequencing data for the 67 unsolved families against an updated panel for developmental glaucoma comprising 52 genes. The genetic cause for disease was identified in an additional five families, with variants in SLC4A11, FOXC1, THBS1, GJA8 and CEP164 identified in one family each. This increases the molecular diagnostic rate in this cohort from 31.6% to 36.7%.
SLC4A11, FOXC1 and GJA8 are established causes of developmental glaucoma associated with other ocular and systemic anomalies. However, THBS1 and CEP164 are more recently associated causative genes, and their identification in this independent cohort supports their role in the pathogenesis of this condition. Identification and verification of novel causative genes for developmental glaucoma aids our understanding of the biological pathways that underly anterior segment development and opens potential avenues for therapeutic development.
Lay Abstract
Developmental glaucoma is a potentially blinding condition caused by raised eye pressure in babies and young children. It may be isolated or associated with other developmental problems. Developmental glaucoma is known to have a genetic basis, with causative genes including CYP1B1, FOXC1, PAX6 and SLC4A11. However, the causative gene is identified in less than a quarter of UK patients with developmental glaucoma.
The 100,000 Genomes Project (100KGP) is a national study of families with rare diseases and cancer who underwent whole genome sequencing (in-depth genetic testing) to aid research into the genetic basis of these conditions. There were 98 families with developmental glaucoma included in 100KGP, of whom 67 remain without a genetic diagnosis (unsolved).
In the past decade, 44 new genes have been identified that can cause developmental glaucoma. We re-evaluated the genetic data for the 67 unsolved families in 100KGP against these 44 genes, along with another 18 long-established causative genes. The genetic cause for developmental glaucoma was identified in five families, with variants in the genes SLC4A11, FOXC1, THBS1, GJA8 and CEP164 identified in one family each. This increases the genetic diagnostic rate in this group from 31.6% to 36.7%.
| Lay Title | Improving the rate of genetic diagnosis for developmental glaucoma in the 100,000 Genomes Project |
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| Role | PhD Student |