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New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Legati, Andrea 
Reyes, Aurelio 
Nasca, Alessia 
Invernizzi, Federica 
Lamantea, Eleonora 

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.

Description

Keywords

E4F1, Mitochondrial disorders, Next Generation Sequencing, Whole Exome sequencing, Adolescent, Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, DNA, Mitochondrial, Electron Transport, Electron Transport Chain Complex Proteins, Exome, Female, Gene Expression, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Molecular Sequence Data, Mutation, Repressor Proteins, Sequence Alignment, Ubiquitin-Protein Ligases, Young Adult

Journal Title

Biochim Biophys Acta

Conference Name

Journal ISSN

0006-3002
1879-2650

Volume Title

1857

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_U105674181)
European Research Council (322424)