Mitochondrial Disease Genetics

Primary mitochondrial diseases are a variable set of energy deficiency disorders with a highly diverse range of clinical symptoms, age of onset, severity, progression, and genetic etiologies. Mitochondria are cellular organelles in which oxidative phosphorylation occurs to generate chemical energy in the form of adenosine triphosphate (ATP). Both nuclear and mitochondrial DNA genomes contribute to approximately 1500 proteins that comprise mitochondria. Since the first genetic etiology of a mitochondrial disease was identified three decades ago, pathogenic variants have now been identified in more than 350 genes across both genomes that cause primary mitochondrial disease with inheritance following every potential inheritance pattern. With the advent, increased uptake and decreased cost of highly sensitive molecular diagnostic testing, along with improved understanding of mitochondrial disease manifestations and pathomechanisms, more and more individuals with suspected mitochondrial disease now receive a definitive genetic diagnosis. Mitochondrial disease treatment options are currently limited but are increasingly personalized to a given patient’s precise genetic etiology. In this chapter, we will review nuclear and mitochondrial genetic etiologies and major categories of mitochondrial disease, genetic diagnostic testing options and methodologies, as well as variant curation approaches and database deposition relevant for primary mitochondrial diseases.