Description
Disruption of genes essential to early eye development may lead to anophthalmia or microphthalmia (A/M) which are characterised by absent or underdeveloped eyes, respectively. A/M are clinically and genetically heterogeneous, with their aetiology still not fully understood. This results in a low molecular diagnostic rate (~20–30%), limiting clinical management and genetic counselling. Furthermore, pathogenic variants may remain undetected due to incomplete gene panels and variant interpretation deficiencies. This study aimed to increase the yield of A/M pathogenic variant identification by implementing an enhanced variant-investigation framework.
We curated an updated A/M gene panel of 160 genes through a systematic literature review, and screened for rare loss-of-function, missense, splicing, and structural variants, which were annotated using deep-learning tools (AlphaMissense, SpliceAI) and other in silico predictors (REVEL, Missense3D, and molecular dynamics simulations). We identified candidate variants in 35 probands, increasing the candidate detection rate from 15.5% (44/283) to 27.9% (79/283). Across the 160 A/M-associated genes in our panel, variants occurred most frequently in established A/M genes, but we also strengthened genotype-phenotype correlations with weaker A/M genes such as ACTG1, DYRK1A, HDAC6, RERE and SIX3. We also identified multiple variants in syndromic participants in the genes CAMK2B, NR2F1 and TRAF7, which have not previously been associated with A/M. We therefore propose these genes as novel candidate A/M genes, contributing to the congenital eye phenotype within the context of their respective syndromic presentations.
This study increased the yield of A/M pathogenic variants, strengthened genotype-phenotype correlations, by implementing an enhanced variant-investigation framework integrating a curated gene panel, comprehensive variant detection pipelines, and advanced in silico analysis. Furthermore, we propose 3 novel candidate A/M genes. Nonetheless, the modest diagnostic rate highlights the genetic complexity of A/M and the ongoing need for improved functional annotation and discovery of additional disease-relevant loci.
Lay Abstract
Anophthalmia and microphthalmia (A/M) are rare conditions where one or both eyes are missing or significantly smaller. These conditions vary greatly between individuals, and consultants often struggle to find a clear genetic explanation, meaning few people with A/M currently receive a genetic diagnosis. This makes it difficult to provide patients with appropriate care and genetic counselling.
To improve genetic diagnosis in this cohort, we studied the DNA of 283 families with A/M from the 100,000 Genomes Project. To interpret identified mutations, we used advanced computer-based tools, including artificial intelligence models. Using this approach, we identified potential disease-causing mutations in 35 families, increasing the detection rate from 15.5% (44/283) to 27.9% (79/283). We also identified multiple mutations in three genes, CAMK2B, NR2F1, and TRAF7, not previously associated with A/M. These were found in individuals with broader syndromes, suggesting these genes may represent new candidate causes of A/M where the eye condition occurs as part of wider clinical features.
This research improves the likelihood that families receive an explanation for A/M while advancing understanding of eye development. Together, these insights support better diagnosis, inform genetic counselling, and supports the development of future research and potential therapies.
| Lay Title | Uncovering the genetic causes of developmental eye globe defects |
|---|---|
| Role | PhD Student |