The identification of causal variants in nystagmus and primary open-angle glaucoma patients through analyses of next-generation sequencing data

Abstract

Background

As next-generation sequencing (NGS) becomes more feasible and accessible, its application in medical genetics becomes increasingly prevalent. Ophthalmic diseases including primary open-angle glaucoma (POAG), oculocutaneous albinism and nystagmus have a strong underlying genetic basis. Understanding the genetic basis is therefore important to facilitate early diagnoses, and aid clinicians in directing targetted treatment to provide best outcome for patients. The molecular basis remains undetermined for many patients. However, high-throughput sequencing and development of bioinformatic tools to process such data has enabled a robust capacity to identify likely causal variants in disease.

Aims

By analysing targetted and whole-exome sequencing (WES) data on patients individually and across cohorts, this thesis aims to interrogate candidate genes which are known or predicted to be causal in POAG, albinism and nystagmus. From these analyses, much needed further insight into causal variants underpinning these ophthalmic diseases can be provided and, importantly, a molecular diagnosis for the patients involved in this work could be ascertained.

Outcomes

The work presented demonstrate herein the importance of TYR tri-allelic genotype in oculocutaneous albinism. With the realisation of its importance in molecular diagnosis of oculocutaneous albinism, it was demonstrated how the tri-allelic TYR genotype could be successfully incorporated into a diagnostic workflow. Furthermore, we were also able to demonstrate that by employing a similar workflow across consanguineous Pakistani ophthalmic disease patients, comparably high diagnostic yields were returned. This thesis confirms that 3.07% of British patients with POAG had likely causal variants in the coding region of the most common causal POAG gene, myocilin (MYOC). Therefore, genetic testing for patients in MYOC coding sequences (namely exon 3) remains the most efficient plan of action when screening this gene. Other known Mendelian-like genes in POAG were able to further account for POAG in 1.17% of the UK POAG cohort. Functional assessment and larger samples sizes are required to test new hypotheses implicating molecular pathologies and other genes as Mendelian-like.

Conclusion

This thesis has expanded on the known molecular genetics underpinning ophthalmic diseases. Importantly, this work has informed clinicians and geneticists on diagnostic workflows and the variants which should be considered in order to achieve successful molecular diagnoses in patients. Crucially, for many of the cases detailed in this work, a molecular diagnosis has successfully been made which will ultimately help ensure the best possible care for the patients involved.

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Identifiers

ORCID for Sarah Ennis: orcid.org/0000-0003-2648-0869

ORCID for Jane Gibson: orcid.org/0000-0002-0973-8285

ORCID for James Self: orcid.org/0000-0002-1030-9963

ORCID for Andrew Lotery: orcid.org/0000-0001-5541-4305

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