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pipelines, until the phenotypes changes [245] . In disease with heterogenous genetic and phenotypes involved,
the diagnostic yield of using the WES or WGS data ranges from 15% to 50% depending on the options
used during the inclusion, selection, and stringency criteria of the analysis. The results also depend on the
status of the knowledge and genetic databases on the time of sampling, as this research area is continually
expanding [245,246] . Previous studies showed a significant improvement in the diagnostic yield if the patient’s
genomic data is re-analyzed again with an improved bioinformatics pipeline [247,248] . Therefore, a periodic re-
analysis of the WES or WSG data in one or two years will improve the identification of the disease-causing
mutations.

The most important issue is the plausibility and effectiveness of these applications for routine diagnostics of
mitochondrial disease. To run all these high-throughput technologies needs high expertise and advanced
machine, which are simply not possible for most of the community clinics. Until there is some development
on the cutting-edge technologies to deliver the same comprehensive results as the NGS, but with a far less
expensive machine, this issue remains a challenge. Another associated problem is the clinical interpretation
of the variants or mutations of unknown significant found from the WES or WGS, which can be confusing
to the clinicians even with a genetic counseling background. Thus, the existence of the Clinical Genome
Resource [249] and ClinVar [250] online databases help in terms of the interpretation of the genomic variants for
the clinicians, which are based on the functional characterization of those variants in various disease models.
Despite these challenges, NGS tools are already being used to diagnose mitochondrial diseases in many
laboratories, as the potential for screening and diagnosis outweigh the downsides of these applications.

MITOCHONDRIAL DNA GENETIC TESTING AVAILABLE ON THE MARKET
Several genetic testing approaches are available on the market nowadays. Here, we discuss the availability
of genetic testing for mitochondrial diseases. Centogene is one of the rare disease companies that offer
testing for 6,500 genes, which is facilitated by highly innovative analytical platforms based on genomics,
proteomics, and metabolomics (https://www.centogene.com). Another company, GeneDX, founded in
2000 by two researchers from the National Institute of Health (NIH), USA, was known as a world genomic
leader due to their expertise in a rare and ultra-rare genetic disorder analysis. They offer services for the
identification of 20,000 genes and hundreds of rare diseases. Also, they offer the chromosomal abnormalities
test (https://www.genedx.com). Family Tree DNA is based in Houston, Texas. They provide services for
mitochondrial diseases, for example, the autosomal DNA testing, Y DNA testing, and mtDNA testing (http://
www.familytreedna.com). Genebase is one of the established direct-to-consumer (DTC) personal genomics
company founded in 2005 based in Vancouver, Canada. Genebase received the world’s prestigious DNA
laboratory accreditations, such as the American Association of Blood Banks (AABB), College of American
Pathology (CAP), Clinical Laboratory Improvement Amendments (CLIA), and ISO17025 for their services
(https://www.genebase.com). 23andMe is also a DTC company, and they offer a simple DNA test from saliva,
which can be done at home. They provide the test kit for analysis with all the DNA information directly to
the customers (https://www.23andme.com). YSEQ company was established in 2013 by Thomas and Astrid
Krahn, which offer several platforms for ancestry study and testing, such as Y-SNPs, Y-STRs, and whole-
genome testing with an application for rare disease (https://www.yseq.net/). FullGenomes is one of the DTC
company founded in 2013 to make NGS technology possible for the public. They offer products such as
whole-genome sequencing and interpretation (SNP, STR, and phylogeny) (https://www.fullgenomes.com).
Living DNA was founded in 2016 by David and Hannah Nicholson to provide a DTC NGS screening kit
(https://livingdna.com). Oxford Ancestors was founded in 2000 by Prof. Bryan Sykes, and they provide the
test for mtDNA maternal and yDNA for paternal ancestry (http://www.oxfordancestors.com) [Table 3].

CONCLUSION
Mitochondrial diseases are complex and clinically heterogeneous, making early diagnosis difficult. Advances
in omics technology, particularly genomics, NGS via targeted mtDNA genome of WES and WGS enable