Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 9, 400

Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause


Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause

Tom E J Theunissen et al. Front Genet.


Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-panels. We conclude that WES is preferable to panel-based approaches for both groups of patients, as the mitochondrial gene-list is not complete and mitochondrial symptoms can be secondary. Also, clinically and genetically heterogeneous disorders would require sequential use of multiple different gene panels. We conclude that WES is a comprehensive and unbiased approach to establish a genetic diagnosis in these patients, able to resolve multi-genic disease-causes.

Keywords: diagnostic yield; mitochondrial disease; mtDNA sequencing; next-generation sequencing; whole-exome sequencing.


Figure 1
Figure 1
The diagnostic yield of mtDNA and whole exome sequencing in a patient cohort consisting of 117 patients. 20% of the patients were solved with a mtDNA defect and 49% with a nuclear DNA defect, implying an overall diagnostic yield of 68%.

Similar articles

See all similar articles

Cited by 3 articles


    1. Acehan D., Vaz F., Houtkooper R. H., James J., Moore V., Tokunaga C., et al. . (2011). Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J. Biol. Chem. 286, 899–908. 10.1074/jbc.M110.171439 - DOI - PMC - PubMed
    1. Alston C. L., Rocha M. C., Lax N. Z., Turnbull D. M., Taylor R. W. (2017). The genetics and pathology of mitochondrial disease. J. Pathol. 241, 236–250. 10.1002/path.4809 - DOI - PMC - PubMed
    1. Andrews B., Carroll J., Ding S., Fearnley I. M., Walker J. E. (2013). Assembly factors for the membrane arm of human complex I. Proc. Natl. Acad. Sci. U. S. A. 110, 18934–18939. 10.1073/pnas.1319247110 - DOI - PMC - PubMed
    1. Antonicka H., Ostergaard E., Sasarman F., Weraarpachai W., Wibrand F., Pedersen A. M., et al. . (2010). Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am. J. Hum. Genet. 87, 115–122. 10.1016/j.ajhg.2010.06.004 - DOI - PMC - PubMed
    1. Bonnen P. E., Yarham J. W., Besse A., Wu P., Faqeih E. A., Al-Asmari A. M., et al. . (2013). Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am. J. Hum. Genet. 93, 471–481. 10.1016/j.ajhg.2013.07.017 - DOI - PMC - PubMed

LinkOut - more resources