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dc.contributor.authorLegati, Andrea
dc.contributor.authorReyes, Aurelio
dc.contributor.authorNasca, Alessia
dc.contributor.authorInvernizzi, Federica
dc.contributor.authorLamantea, Eleonora
dc.contributor.authorTiranti, Valeria
dc.contributor.authorGaravaglia, Barbara
dc.contributor.authorLamperti, Costanza
dc.contributor.authorArdissone, Anna
dc.contributor.authorMoroni, Isabella
dc.contributor.authorRobinson, Alan
dc.contributor.authorGhezzi, Daniele
dc.contributor.authorZeviani, Massimo
dc.date.accessioned2019-07-03T13:36:32Z
dc.date.available2019-07-03T13:36:32Z
dc.date.issued2016-08
dc.identifier.issn0006-3002
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/294309
dc.description.abstractNext 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.language.isoen
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMitochondria
dc.subjectHumans
dc.subjectMitochondrial Diseases
dc.subjectUbiquitin-Protein Ligases
dc.subjectElectron Transport Chain Complex Proteins
dc.subjectRepressor Proteins
dc.subjectDNA, Mitochondrial
dc.subjectCohort Studies
dc.subjectSequence Alignment
dc.subjectGene Expression
dc.subjectAmino Acid Sequence
dc.subjectElectron Transport
dc.subjectHeterozygote
dc.subjectHomozygote
dc.subjectMutation
dc.subjectMolecular Sequence Data
dc.subjectAdolescent
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectInfant
dc.subjectFemale
dc.subjectMale
dc.subjectYoung Adult
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectExome
dc.titleNew genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies.
dc.typeArticle
prism.endingPage1335
prism.issueIdentifier8
prism.publicationDate2016
prism.publicationNameBiochim Biophys Acta
prism.startingPage1326
prism.volume1857
dc.identifier.doi10.17863/CAM.41407
dcterms.dateAccepted2016-02-27
rioxxterms.versionofrecord10.1016/j.bbabio.2016.02.022
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-08
dc.contributor.orcidReyes Tellez, Aurelio [0000-0003-2876-2202]
dc.contributor.orcidRobinson, Alan [0000-0001-9943-0059]
dc.identifier.eissn1879-2650
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UP_1002/1)
pubs.funder-project-idMedical Research Council (MC_U105674181)
pubs.funder-project-idEuropean Research Council (322424)
cam.issuedOnline2016-03-08


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Attribution-NonCommercial-NoDerivatives 4.0 International
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