| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Invernizzi, Federica Reyes, Aurelio Lamperti, Costanza Robinson, Alan Ghezzi, Daniele Tiranti, Valeria Legati, Andrea Moroni, Isabella Nasca, Alessia Garavaglia, Barbara Zeviani, Massimo Lamantea, Eleonora Ardissone, Anna |
| Description |
Author Affiliation: Legati A ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Reyes A ( Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.); Nasca A ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Invernizzi F ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Lamantea E ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Tiranti V ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Garavaglia B ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Lamperti C ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy.); Ardissone A ( Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.); Moroni I ( Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20133 Milan, Italy.); Robinson A ( Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.); Ghezzi D ( Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', 20126 Milan, Italy. Electronic address: dghezzi@istituto-besta.it.); Zeviani M ( Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK. Electronic address: mdz21@mrc-mbu.cam.ac.uk.) |
| 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. |
| ISSN |
00063002 |
| Journal |
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number |
8 |
| Volume Number |
1857 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2016-08-01 |
| Publisher Place |
Netherlands |
| Access Restriction |
Open |
| Subject Keyword |
DNA, Mitochondrial Genetics Electron Transport Chain Complex Proteins Mitochondria Metabolism Mitochondrial Diseases Mutation Repressor Proteins Adolescent Amino Acid Sequence Child, Preschool Cohort Studies Electron Transport Exome Gene Expression Heterozygote High-Throughput Nucleotide Sequencing Homozygote Infant Pathology Diagnosis Molecular Sequence Data Sequence Alignment Research Support, Non-U.S. Gov't Biochemistry |
| Content Type |
Text |
| Resource Type |
Article |
