New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies.
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Authors
Legati, Andrea
Nasca, Alessia
Invernizzi, Federica
Lamantea, Eleonora
Tiranti, Valeria
Garavaglia, Barbara
Lamperti, Costanza
Ardissone, Anna
Moroni, Isabella
Ghezzi, Daniele
Zeviani, Massimo
Publication Date
2016-08Journal Title
Biochim Biophys Acta
ISSN
0006-3002
Publisher
Elsevier BV
Volume
1857
Issue
8
Pages
1326-1335
Language
English
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Legati, A., Reyes Tellez, A., Nasca, A., Invernizzi, F., Lamantea, E., Tiranti, V., Garavaglia, B., et al. (2016). New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies.. Biochim Biophys Acta, 1857 (8), 1326-1335. https://doi.org/10.1016/j.bbabio.2016.02.022
Abstract
Next Generation Sequencing (NGS) technologies are revolutionizing the diagnostic screening for rare disease entities, including primary mitochondrial disorders, particularly those caused by nuclear gene defects. NGS approaches are able to identify the causative gene defects in small families and even single individuals, unsuitable for investigation by traditional linkage analysis. These technologies are contributing to fill the gap between mitochondrial disease cases defined on the basis of clinical, neuroimaging and biochemical readouts, which still outnumber by approximately 50% the cases for which a molecular-genetic diagnosis is attained. We have been using a combined, two-step strategy, based on targeted genes panel as a first NGS screening, followed by whole exome sequencing (WES) in still unsolved cases, to analyze a large cohort of subjects, that failed to show mutations in mtDNA and in ad hoc sets of specific nuclear genes, sequenced by the Sanger's method. Not only this approach has allowed us to reach molecular diagnosis in a significant fraction (20%) of these difficult cases, but it has also revealed unexpected and conceptually new findings. These include the possibility of marked variable penetrance of recessive mutations, the identification of large-scale DNA rearrangements, which explain spuriously heterozygous cases, and the association of mutations in known genes with unusual, previously unreported clinical phenotypes. Importantly, WES on selected cases has unraveled the presence of pathogenic mutations in genes encoding non-mitochondrial proteins (e.g. the transcription factor E4F1), an observation that further expands the intricate genetics of mitochondrial disease and suggests a new area of investigation in mitochondrial medicine. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
Keywords
Mitochondria, Humans, Mitochondrial Diseases, Ubiquitin-Protein Ligases, Electron Transport Chain Complex Proteins, Repressor Proteins, DNA, Mitochondrial, Cohort Studies, Sequence Alignment, Gene Expression, Amino Acid Sequence, Electron Transport, Heterozygote, Homozygote, Mutation, Molecular Sequence Data, Adolescent, Child, Child, Preschool, Infant, Female, Male, Young Adult, High-Throughput Nucleotide Sequencing, Exome
Sponsorship
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_U105674181)
European Research Council (322424)
Identifiers
External DOI: https://doi.org/10.1016/j.bbabio.2016.02.022
This record's URL: https://www.repository.cam.ac.uk/handle/1810/294309
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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