Description
Microphthalmia is a rare congenital eye defect characterised by a small, underdeveloped eye. Notably, microphthalmia exhibits genetic heterogeneity, in which mutations in different genes can result in a similar clinical phenotype. Although gene panel testing covering 147 genes is currently used by clinicians in the United Kingdom for the genetic diagnosis of microphthalmia, approximately 70% of patients remain without a molecular diagnosis. This highlights the need to identify additional genes associated with the condition. By examining the de novo variants within the unresolved microphthalmia cohort recorded in Genomics England, we identified an individual with severe microphthalmia who had a heterozygous missense variant in CCNC. Further examination of the variant suggests that this change is rare with predicted pathogenicity. CCNC is a non-cycling cyclin that involves in transcription activity regulation in metazoan. To examine the effect of CCNC on eye development in vivo, we established a ccnc zebrafish mutant line using CRISPR/Cas9-mediated mutagenesis. ccnc disrupted embryos showed significant reduction in eye diameter, resembling the microphthalmia phenotype observed in the human proband. Together, these results support CCNC as a novel microphthalmia-associated gene in vertebrates.
Lay Abstract
Our eyes develop from a structure called the optic vesicle. If the optic vesicle does not grow correctly, this results in microphthalmia (a small, underdeveloped eye). Microphthalmia is the cause of approximately 3.2%-11.2% of childhood blindness worldwide. So far, 40 genes have been identified that can cause microphthalmia, but these only account for about 30% of cases. Further research is needed to identify more of the genes that cause this condition.
We used whole genome sequencing (in-depth genetic testing) to look for changes in other genes in patients with microphthalmia. Using this technique, we identified one patient with a change in a gene called Cyclin-C (CCNC), which is known to contribute to eye growth in fruit flies. To confirm this, we blocked the action of the ccnc gene in zebrafish embryos. This resulted in the affected zebrafish growing smaller eyes than normal. This supports the role of CCNC as a gene that contributes to eye growth in humans and can cause microphthalmia.
| Lay Title | Changes in CCNC gene linked to small eye development |
|---|---|
| Role | Postdoctoral Researcher |