The switch in the diagnosis of mitochondrial diseases from the classical ‘function first’ to the NGS-based ‘genetics first’ diagnostic era

The knowledge of causes and pathophysiology of mitochondrial diseases has increased exponentially in the last four decades. Recently, due to the decreased costs of new sequencing technologies (exome and whole genome sequencing), these technologies were applied more and more in clinical routine. The traditional diagnostic approach (‘biopsy first’) of evaluating the patient and his body fluids and the analysis of enzymes of the oxidative phosphorylation system in skeletal muscle with subsequent Sanger sequencing of single candidate genes (‘from function to gene’) were replaced by next generation sequencing techniques with a diagnostic yield of >40%. In this ‘genetics first’ approach, the detection of new candidate genes necessitates often functional evaluations (‘from gene to function’) leading to reverse phenotyping of affected individuals. The new genetic era has offered a clear new challenge for the responsibility of the diagnostic centres: the interplay of clinicians, geneticists and functional biochemists is a prerequisite for a validated diagnosis. It becomes evident that expanded diagnostics builds an interface to research. Only competence centres with high numbers of patients, clinical and diagnostic experience and exchange of knowledge with other comparable units can fulfil all those requirements.