Increasing the molecular diagnosis rate of anophthalmia and microphthalmia: Identification and validation of new genomic variants

Brief Lay background

Anophthalmia (A, absent eyes) and microphthalmia (M, small eye) are congenital eye malformations responsible for ~11% of childhood blindness. As the morphological defects of A/M cannot be corrected, there is no cure. However, learning more about the function of genes that cause A/M when mutated could enable the development of therapies for this condition.

Although variants in many genes have been linked to A/M, the genetic diagnosis rate remains low, reaching only ~20%, and suggesting that more genes are yet to be identified. One of the main challenges in improving the genetic diagnosis of A/M is that, being a rare disease, with an incidence of 1 in 20.000 live births, makes it difficult to recruit enough patients for genetic testing. Therefore, recruiting more patients for genetic studies is essential to demonstrate that a given mutated gene is linked to multiple cases, which would help increase the diagnosis rate of A/M.

What problem/knowledge gap does it help address

Identifying and validating new genes associated with A/M is a fundamental step towards increasing the diagnosis rate of A/M and enabling appropriate genetic counselling, patient care and the development of preventive therapies. However, linking new genes to A/M poses two main challenges. Accessing enough patients to demonstrate the causality. Successfully showing in animal or in vitro models that mutating the identified gene impairs eye formation.

Our team has curated a cohort of 264 genetically undiagnosed A/M patients and relatives present in the UK- 100,000 genomes project (100KGP). We are studying these cases to identify new genes linked to A/M.

Due to compensatory mechanisms, mutations in A/M genes often show no eye defects in animal models. To address this, we have developed novel tools in zebrafish to determine which steps of eye development are specifically impaired when A/M-linked genes are knocked down, revealing gene functions that would otherwise be missed.

Aim of the project

To increase the diagnosis rate of A/M by identifying new A/M-related variants in the genomes of over 250 patients recruited to the 100KGP and validating their pathogenicity in eye development using zebrafish and organoid models.

Potential impact on people with sight loss

Although A/M cannot be cured, identifying the pathogenic gene variant can significantly improve the quality of life for patients and their families. A/M is often associated with other medical conditions, such as endocrinological defects, which can be managed after genetic diagnosis. Furthermore, identifying the causative gene variants offers psychological closure and aids family planning by clarifying inheritance patterns. Throughout the project, starting one year in, the team will confirm new pathogenic gene variants and inform treating consultants. These efforts aim to enhance patient outcomes and provide valuable guidance for both medical and personal decisions.