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Mitochondrial disease genetics update

recent insights into the molecular diagnosis and expanding phenotype of primary mitochondrial disease

McCormick, Elizabeth M.a,*; Zolkipli-Cunningham, Zarazuelaa,*; Falk, Marni J.a,b

doi: 10.1097/MOP.0000000000000686
GENETICS: Edited by Nathaniel H. Robin

Purpose of review Primary mitochondrial disease (PMD) is a genetically and phenotypically diverse group of inherited energy deficiency disorders caused by impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity. Mutations in more than 350 genes in both mitochondrial and nuclear genomes are now recognized to cause primary mitochondrial disease following every inheritance pattern. Next-generation sequencing technologies have dramatically accelerated mitochondrial disease gene discovery and diagnostic yield. Here, we provide an up-to-date review of recently identified, novel mitochondrial disease genes and/or pathogenic variants that directly impair mitochondrial structure, dynamics, and/or function.

Recent findings A review of PubMed publications was performed from the past 12 months that identified 16 new PMD genes and/or pathogenic variants, and recognition of expanded phenotypes for a wide variety of mitochondrial disease genes.

Summary Broad-based exome sequencing has become the standard first-line diagnostic approach for PMD. This has facilitated more rapid and accurate disease identification, and greatly expanded understanding of the wide spectrum of potential clinical phenotypes. A comprehensive dual-genome sequencing approach to PMD diagnosis continues to improve diagnostic yield, advance understanding of mitochondrial physiology, and provide strong potential to develop precision therapeutics targeted to diverse aspects of mitochondrial disease pathophysiology.

aMitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia

bDepartment of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

Correspondence to Marni J. Falk, ARC 1002c, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA. Tel: +1 215 590 4564; e-mail:

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