Description
Microphthalmia, anophthalmia, and coloboma (MAC) are developmental eye disorders that remain one of the major causes of childhood blindness, affecting 1 to 4 in every 10,000 live births. While genetic heterogeneity of the MAC clinical spectrum is well recognised, many cases still lack an identifiable genetic diagnosis. Vitamin A deficiency has been highlighted as an environmental cause for MAC in previous cases, yet the effect of vitamin A metabolic gene variants has not been systematically examined.
Using the Genomics England 100,000 Genome Project dataset, this project aims to identify candidate genes linked to both vitamin A pathways and MAC condition and integrate these with patient-level genomic and phenotypic data to uncover novel gene–disease associations. An initial set of 71 genes were prioritised through Gene Ontology-based filtering, while 237 individuals were identified with unresolved MAC spectrum disorders as target cohort. Subsequent variants filtering yielded 34 single-nucleotide variants in candidate genes with a maximum allele frequency <0.05%.
Future work is to systematically filter rare variants for their predicted pathogenicity and evaluate these through a case-to-case analysis. Functional validation of these variants will be done by zebrafish mutagenesis. This project will ultimately provide new insights into the underlying molecular mechanisms of the MAC spectrum.
Lay Abstract
Small eyes (microphthalmia), missing eyes (anophthalmia), or gaps in eye structures (coloboma) are collectively known as the MAC spectrum. These conditions are present from birth and are major causes of childhood blindness. Although many genes have already been linked to these disorders, most MAC cases still lack a genetic diagnosis.
Vitamin A is a key nutrient required for normal eye development. This project aims to better understand the underlying causes of the MAC spectrum by investigating changes in genes that affect vitamin A processing during eye development. First, genes involved in vitamin A metabolism and eye growth were identified from previous research studies. The genetic data from a group of patients with MAC spectrum disorders was then analysed, looking for any changes in these genes.
Through this approach, several genetic changes that may cause MAC spectrum have been preliminarily identified in affected patients. The impact of these genetic changes will be tested by blocking the function of each gene in zebrafish to see whether this results in small, absent or incomplete eye development. This work will help improve genetic diagnosis rates for MAC patients and deepen our understanding of eye formation.
| Lay Title | Investigating DNA Changes Affecting Vitamin A Processing in Rare Eye Diseases |
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| Role | Master Student |