The successful introduction of next generation sequencing (NGS) in combination with the availability of large collections of well-phenotyped patients in national registries and attached biomaterial has dramatically improved the diagnostic yield for mitochondrial diseases. Whole exome sequencing (WES) not only provided the diagnosis of mutations in , but has enabled the identification of a constantly growing list of new disease genes, thereby setting the ground to uncover pathophysiologic disease mechanisms and evaluate targeted therapeutic approaches. Although molecular diagnostics for mitochondrial disorders by WES are well-established, approximately 50% of patients remain without a clear genetic diagnosis. There are four areas for improving diagnostic rates by:
i) the integration of “Human Phenotype Ontology” (HPO) from the patient registries,
ii) increasing power through increased number of datasets,
iii) advanced use of a patient’s full genetic profile, and
iv) variant annotation and feed-back to clinical databases.