Whole exome sequencing of suspected mitochondrial patients in clinical practice
Open accessAbstract
Mitochondrial disorders are characterized by a broad clinical spectrum. Identical clinical signs and symptoms can be caused by mutations in different mitochondrial or nuclear genes. Vice versa, the same mutation can lead to different phenotypes. Genetic syndromes and neuromuscular disorders mimicking mitochondrial disorders further complicate the diagnostic process. Whole exome sequencing (WES) is the state of the art next generation sequencing technique to identify genetic defects in mitochondrial disorders. Until recently it has mainly been used as a research tool. In this study, the use of WES in routine diagnostics is described. The WES data of 109 patients, referred under the suspicion of a mitochondrial disorder, were examined in two steps. First, the data were filtered using a virtual gene panel of genes known to be associated with mitochondrial disease. If negative, the entire exome was examined. A molecular diagnosis was achieved in 39 % of the heterogeneous cohort, and in 57 % of the subgroup of 42 patients with the highest suspicion for a mitochondrial disease. In addition to mutations in genes known to be associated with mitochondrial disorders (e.g. TUFM, MTFMT, FBXL4), in the subgroup of patients with the lowest suspicion for a mitochondrial disorder we found mutations in several genes associated with neuromuscular disorders (e.g. SEPN1, ACTA1) and genetic syndrome (e.g. SETBP1, ARID1B). Our results show that WES technology has been successfully implemented as a state‐of‐the‐art, molecular diagnostic test for mitochondrial disorders as well as for the mimicking disorders in daily clinical practice. It also illustrates that clinical and biochemical phenotyping is essential for successful application of WES to diagnose individual patients.
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Approximately 50-75% of patients with Mendelian disorders do not receive a genetic diagnosis based on WES that could identify disease-causing variants in noncoding regions.
“Approximately 50–75% of patients with Mendelian disorders do not receive a genetic diagnosis based on WES that could identify disease-causing variants in noncoding regions [41,42].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [41]
The Discussion reports that WES diagnosed 42 of 109 patients suspected of having a mitochondrial disorder (39%), leaving approximately 61% without a genetic diagnosis. That supports a figure within the claimed range, but only for this specific cohort; the paper does not establish a 50–75% rate across Mendelian disorders or attribute undiagnosed cases to disease-causing variants in noncoding regions. Page numbers were not provided in our copy. (LLM, conf=0.86)
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- Authors
- Wortmann, S. B., Koolen, D. A., Smeitink, J. A., den van Heuvel, L., & Rodenburg, R. J.
- Affiliations
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Department of Pediatrics Radboudumc, Nijmegen Centre for Mitochondrial Disorders (NCMD) P.O Box 9101 774 Translational Metabolic Laboratory Nijmegen 6500 HB The Netherlands
- Corresponding author
- Rodenburg, Richard J.
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2015-03-04
- Volume
- 38
- Issue
- 3
- Pages
- 437-443
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- PMC
- PMC4432107
- OpenAlex
- W1980589014
- Cited by
- 233
- References
- 39
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 21 · 2023: 17 · 2022: 17 · 2021: 33 · 2020: 28 · 2019: 21 · 2018: 28 · 2017: 24 · 2016: 17 · 2015: 5
- FWCI
- 16.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial disease, exome sequencing, molecular diagnosis, diagnostic yield, neuromuscular disorders, genetic syndromes, phenotyping, TUFM, FBXL4, SEPN1, ACTA1, SETBP1, ARID1B
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Mitochondria, Mutation, Phenotype, Sequence Analysis, DNA, Mitochondrial Diseases, Young Adult, High-Throughput Nucleotide Sequencing, Exome
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