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Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

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dc.contributor.authorSchon, Katherine R
dc.contributor.authorHorvath, Rita
dc.contributor.authorWei, Wei
dc.contributor.authorCalabrese, Claudia
dc.contributor.authorTucci, Arianna
dc.contributor.authorIbañez, Kristina
dc.contributor.authorRatnaike, Thiloka
dc.contributor.authorPitceathly, Robert D S
dc.contributor.authorBugiardini, Enrico
dc.contributor.authorQuinlivan, Rosaline
dc.contributor.authorHanna, Michael G
dc.contributor.authorClement, Emma
dc.contributor.authorAshton, Emma
dc.contributor.authorSayer, John A
dc.contributor.authorBrennan, Paul
dc.contributor.authorJosifova, Dragana
dc.contributor.authorIzatt, Louise
dc.contributor.authorFratter, Carl
dc.contributor.authorNesbitt, Victoria
dc.contributor.authorBarrett, Timothy
dc.contributor.authorMcMullen, Dominic J
dc.contributor.authorSmith, Audrey
dc.contributor.authorDeshpande, Charulata
dc.contributor.authorSmithson, Sarah F
dc.contributor.authorFestenstein, Richard
dc.contributor.authorCanham, Natalie
dc.contributor.authorCaulfield, Mark
dc.contributor.authorHoulden, Henry
dc.contributor.authorRahman(, Shamima
dc.contributor.authorChinnery, Patrick F
dc.contributor.authorGenomics England Research Consortium
dc.contributor.authorAmbrose, John C
dc.contributor.authorArumugam, Prabhu
dc.contributor.authorBevers, Roel
dc.contributor.authorBleda, Marta
dc.contributor.authorBoardman-Pretty, Freya
dc.contributor.authorBoustred, Christopher R
dc.contributor.authorBrittain, Helen
dc.contributor.authorCaulfield, Mark J
dc.contributor.authorChan, Georgia C
dc.contributor.authorElgar, Greg
dc.contributor.authorFowler, Tom
dc.contributor.authorGiess, Adam
dc.contributor.authorHamblin, Angela
dc.contributor.authorHenderson, Shirley
dc.contributor.authorHubbard, Tim J P
dc.contributor.authorJackson, Rob
dc.contributor.authorJones, Louise J
dc.contributor.authorKasperaviciute, Dalia
dc.contributor.authorKayikci, Melis
dc.contributor.authorKousathanas, Athanasios
dc.contributor.authorLahnstein, Lea
dc.contributor.authorLeigh, Sarah E A
dc.contributor.authorLeong, Ivonne U S
dc.contributor.authorLopez, Javier F
dc.contributor.authorMaleady-Crowe, Fiona
dc.contributor.authorMcEntegart, Meriel
dc.contributor.authorMinneci, Federico
dc.contributor.authorMoutsianas, Loukas
dc.contributor.authorMueller, Michael
dc.contributor.authorMurugaesu, Nirupa
dc.contributor.authorNeed, Anna C
dc.contributor.authorO’Donovan, Peter
dc.contributor.authorOdhams, Chris A
dc.contributor.authorPatch, Christine
dc.contributor.authorBuonerimo Pereira, Mariana
dc.contributor.authorPerez-Gil, Daniel
dc.contributor.authorPullinger, John
dc.contributor.authorRahim, Tahrima
dc.contributor.authorRendon, Augusto
dc.contributor.authorRogers, Tim
dc.contributor.authorSavage, Kevin
dc.contributor.authorSawant, Kushmita
dc.contributor.authorScott, Richard H
dc.contributor.authorSiddiq, Afshan
dc.contributor.authorSieghart, Alexander
dc.contributor.authorSmith, Samuel C
dc.contributor.authorSosinsky, Alona
dc.contributor.authorStuckey, Alexander
dc.contributor.authorTanguy, Mélanie
dc.contributor.authorTaylor Tavares, Ana Lisa
dc.contributor.authorThomas, Ellen R A
dc.contributor.authorThompson, Simon R
dc.contributor.authorWelland, Matthew J
dc.contributor.authorWilliams, Eleanor
dc.contributor.authorWitkowska, Katarzyna
dc.contributor.authorWood, Suzanne M
dc.contributor.orcidSchon, Katherine R [0000-0001-8054-8954]
dc.contributor.orcidHoulden, Henry [0000-0002-2866-7777]
dc.contributor.orcidRahman(, Shamima [0000-0003-2088-730X]
dc.contributor.orcidChinnery, Patrick F [0000-0002-7065-6617]
dc.date.accessioned2021-11-04T10:20:27Z
dc.date.available2021-11-04T10:20:27Z
dc.date.issued2021-11-03
dc.date.updated2021-11-04T10:20:26Z
dc.descriptionFunder: University of Cambridge; FundRef: http://dx.doi.org/10.13039/501100000735
dc.descriptionFunder: Alzheimer's Society; FundRef: http://dx.doi.org/10.13039/501100000320
dc.descriptionFunder: Leverhulme Trust; FundRef: http://dx.doi.org/10.13039/501100000275
dc.descriptionFunder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272
dc.descriptionFunder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276
dc.descriptionFunder: Evelyn Trust; FundRef: http://dx.doi.org/10.13039/501100004282
dc.descriptionFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440
dc.descriptionFunder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265
dc.description.abstractAbstract: Objective: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. Design: Cohort study. Setting: National Health Service, England, including secondary and tertiary care. Participants: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. Intervention: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. Main outcome measure: Definite or probable genetic diagnosis. Results: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. Conclusion: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.
dc.identifier.doi10.17863/CAM.77724
dc.identifier.eissn1756-1833
dc.identifier.otherbmj-2021-066288.r1
dc.identifier.otherschk066288
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330283
dc.languageen
dc.publisherBritish Medical Journal Publishing Group
dc.subjectResearch
dc.titleUse of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study
dc.typeArticle
dcterms.dateAccepted2021-10-11
prism.publicationNameBMJ
prism.volume375
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1136/bmj-2021-066288

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