Known genes, new genes and new phenotypes in mitochondrial eye diseases

Abstract

Primary mitochondrial diseases together represent a major cause of inherited neurological disorders that, due to dysfunction of the mitochondrial respiratory chain, can affect many parts of body, especially high energy demand organs, such as liver, heart, kidney, muscle and the eye. As the eye is particularly vulnerable to mitochondrial dysfunction, approximately half of all the patients with confirmed mitochondrial disease will develop significant ocular involvement and the complication that patients are most afraid of is visual loss. This can arise either from a primary optic neuropathy (the most common ocular involvement), from outer retinal degeneration, or in some cases from retrochiasmal visual pathway involvement resulting in varying patterns of visual field defects. To date, inherited optic neuropathies have been linked with pathogenic variants in over 40 genes across both the mitochondrial (mtDNA) and nuclear (nDNA) genomes with maternal (mtDNA) inheritance, autosomal dominant, recessive and x‐linked inheritance observed. Inherited optic neuropathies are a significant cause of blindness in both the paediatric and adult population with an estimated prevalence of 1 in 10 000 in the UK. The prevalence is estimated low because of the difficulty in making a confirmed molecular diagnosis due to multiple factors: mutations have been identified in both genomes, a limited number of genes are included in next generation sequencing (NGS) panels, phenocopies etc. Current genetic testing strategies for inherited eye diseases fail to identify pathogenic variants in a significant proportion of cases suggesting that previously unidentified genes harbouring pathogenic variants remain to be identified. However, whole exome sequencing (WES) and particularly whole genome sequencing (WGS), and unbiased interrogation of genomic variants offers an unparalleled opportunity to detect variants in both uncharacterised genes and non‐coding regions of the genome leading to previously unknown gene‐disease associations. This presentation highlights the power of unbiased WGS to elucidate the missing heritability in mitochondrial eye diseases and reports novel gene‐disease associations and novel phenotypes associated with known genes defects.