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

Theunissen, Tom E. J.; Nguyen, Minh; Kamps, Rick; Hendrickx, Alexandra T.M.; Sallevelt, Suzanne C E H; Gottschalk, Ralph W.H.; Calis, Chantal; Stassen, Alphons P. M.; Koning, Bart de; Hartog, Elvira N.M. Mulder-Den; Schoonderwoerd, Kees; Fuchs, Sabine A.; Hilhorst‐Hofstee, Yvonne; Visser, Marjolein; Vanoevelen, Jo; Szklarczyk, Radek; Gerards, Mike; Coo, I.F.M. de; Hellebrekers, Debby M.E.I.; Smeets, Hubert J.M.

doi:10.3389/fgene.2018.00400

Cited by 79 publications

(81 citation statements)

References 87 publications

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“…Taking the specific challenges for diagnosing MD as shown in Table , our data and recent studies claiming for an “exome first” or a combined diagnostic approach to identify mtDNA and nuclear variants in account, we propose that ES from leucocyte derived DNA (blood) should be done as the initial test in all individuals with suspected mitochondrial disease. Hereby, it is important to know the limitations of this method and the necessary follow test as summarized in Figure .…”

Section: Discussionmentioning

confidence: 97%

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

Wagner

Berutti

Lorenz‐Depiereux

et al. 2019

J of Inher Metab Disea

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Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of “off‐target reads” deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues).

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Section: Discussionmentioning

confidence: 97%

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

Wagner

Berutti

Lorenz‐Depiereux

et al. 2019

J of Inher Metab Disea

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“…A rare variant p.P1629L was identified in a patient with myotonia, which was suggested as pathogenic by in silico evaluation . Mutations p.P1650L and p.E1702K have also been reported in patients with myotonia . Thus, the evidence showing that mutations in the CTerm of Nav1.4 are associated with myotonia has been accumulating, although the number of reports is still limited.…”

Section: Discussionmentioning

confidence: 99%

EF hand‐like motif mutations of Nav1.4 C‐terminus cause myotonic syndrome by impairing fast inactivation

et al. 2020

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Introduction: Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce.Methods: We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). Results:The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation.

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“…NGS/MPS can also be used for sequencing of the mitochondrial genome. Although electron transport chain studies have traditionally been used in the diagnosis of mitochondrial diseases, given the ease of use of NGS/MPS studies, the latter are being used progressively more for diagnosis of these diseases (Gai et al., 2013; Götz et al., 2011; Lalani, 2017; Theunissen et al., 2018). In addition, triplet repeat expansion mutations may now be detected using NGS techniques rather than the more cumbersome technique of Southern blotting, opening new avenues for the use of these techniques in genetic diagnosis (Loomis et al., 2013).…”

Section: Multiple Ligation‐dependent Probe Amplification (Mlpa)mentioning

confidence: 99%

An Overview of Molecular Genetic Diagnosis Techniques

Goswami

Harada

2020

CP Human Genetics

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Our understanding of genetic disease(s) has increased exponentially since the completion of human genome sequencing and the development of numerous techniques to detect genetic variants. These techniques have not only allowed us to diagnose genetic disease, but in so doing, also provide increased understanding of the pathogenesis of these diseases to aid in developing appropriate therapeutic options. Additionally, the advent of next‐generation or massively parallel sequencing (NGS/MPS) is increasingly being used in the clinical setting, as it can detect a number of abnormalities from point mutations to chromosomal rearrangements as well as aberrations within the transcriptome. In this article, we will discuss the use of multiple techniques that are used in genetic diagnosis. © 2020 by John Wiley & Sons, Inc.

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

Cited by 79 publications

References 87 publications

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

EF hand‐like motif mutations of Nav1.4 C‐terminus cause myotonic syndrome by impairing fast inactivation

An Overview of Molecular Genetic Diagnosis Techniques

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