Exome sequencing for mitochondrial disease

Improving the genetic diagnosis of mitochondrial diseases

Exome sequencing of patients with mitochondrial disease is a major focus of the Mitochondrial Medicine group, and plays an important role in clinical diagnostic and management strategies. Furthermore, variants identified in novel mitochondrial genes provide valuable insight into mitochondrial function and disease, and can be transferred to diagnostic tests, including high-throughput sequencing.

Currently, whole exome sequencing is successful in diagnosing only around 30% of cases. For some undiagnosed cases, the pathogenic variants may occur in uncharacterised genes. In other cases, the pathogenic variants may be missed for a number of reasons, including: extra-exonic localisation, non-coverage, oligogenic contributions, complex or large-scale insertions, deletions, or rearrangements, or mutations in non-protein coding genes (e.g. microRNAs). 

We have established a pipeline using the Broad's GATK and optimised to identify pathogenic variants in mitochondrial genes, but there is still an urgent and unmet need to improve the identification and prioritisation of candidate mitochondrial disease genes from exome sequencing. So we are developing new methods to improve the analysis of sequencing data for mitochondrial diseases.