Cited by 235Genomics and Rare DiseasesMitochondrial Function and PathologyMetabolism and Genetic Disorders

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Whole exome sequencing of suspected mitochondrial patients in clinical practice

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Wortmann, Saskia B., Koolen, David A., Smeitink, Jan A., den van Heuvel, Lambert, Rodenburg, Richard J.·2015·Journal of Inherited Metabolic Disease

DOI 10.1007/s10545-015-9823-yPMC PMC4432107

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Abstract

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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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)
Corresponding author: Rodenburg, Richard J.
ORCID: Wortmann, Saskia B.
Koolen, David A.
Smeitink, Jan A.
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
DOI: 10.1007/s10545-015-9823-y
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: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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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Whole exome sequencing of suspected mitochondrial patients in clinical practice

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