Description
Anophthalmia and microphthalmia (A/M) are rare developmental eye disorders characterised by the absence or reduced size of the eye, respectively. These conditions are genetically heterogeneous, with over 150 causative genes identified, yet much of their genetic basis remains unresolved, resulting in only 20-30% of affected individuals receiving a genetic diagnosis. This highlights a critical gap in understanding the genetic basis of A/M and the need to identify additional causal variants to improve diagnosis and understanding of the disease.
We investigated unresolved A/M in participants recruited to the 100,000 Genomes Project to identify novel causal genes and improve diagnostic rates. Analysis focused on families with available trio or extended family data, particularly those with more than one affected individual, enhancing segregation analysis. A broad range of variant types were assessed and prioritised, such as SNVs, Indels and structural variants, based on low allele frequency and predicted functional impact using AlphaMissense and SpliceAI tools. Eight candidate variants were identified in two probands. Notably, a pathogenic variant in KIF17 showed strong segregation with disease and a high predicted impact on splicing. As KIF17 has only been associated with microphthalmia in one reported family, this study strengthens the evidence supporting its role in A/M.
Our ongoing work aims to functionally validate candidate genes by CRISPR knockdown in zebrafish to assess their role in eye development and investigate the impact of the identified variants in vivo, providing further insight into disease mechanisms. Ultimately, this study has the potential to increase molecular diagnosis rates in affected individuals, and improve our understanding of A/M and the developmental mechanisms involved in its aetiology.
Lay Abstract
Some people are born with eyes that are either very small (microphthalmia) or completely absent (anophthalmia). These are rare conditions that affect vision because the eye does not develop properly. Although many genes linked to these disorders have already been discovered, most patients still do not receive a clear genetic diagnosis.
Therefore, we wanted to identify novel genetic mutations that might explain why these conditions occur in patients who currently have no diagnosis. We analysed genomic data from patients and their families who took part in a large UK research study called the 100,000 Genomes Project. By comparing the DNA sequences from affected individuals and their relatives, we looked for rare mutations that could be causing these eye phenotypes.
We identified several possible genetic changes that may contribute to A/M. One important finding was a mutation in a gene called KIF17, which has previously only been reported in
one family with this microphthalmia. Our results provide stronger evidence that this gene may play a role in A/M.
This research could help more patients receive a genetic diagnosis in the future. Understanding the genetic causes of these conditions may also improve how we study eye development and could guide future treatments.
| Lay Title | Understanding the Genetic Causes of Rare Eye Development Conditions |
|---|---|
| Role | Master Student |