Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study
Creators: name: Schon, Katherine R
name: Horvath, Rita
name: Wei, Wei
name: Calabrese, Claudia
name: Tucci, Arianna
name: Ibañez, Kristina
name: Ratnaike, Thiloka
name: Pitceathly, Robert D S
name: Bugiardini, Enrico
name: Quinlivan, Rosaline
name: Hanna, Michael G
name: Clement, Emma
name: Ashton, Emma
name: Sayer, John A
name: Brennan, Paul
name: Josifova, Dragana
name: Izatt, Louise
name: Fratter, Carl
name: Nesbitt, Victoria
name: Barrett, Timothy
name: McMullen, Dominic J
name: Smith, Audrey
name: Deshpande, Charulata
name: Smithson, Sarah F
name: Festenstein, Richard
name: Canham, Natalie
name: Caulfield, Mark
name: Houlden, Henry
name: Rahman(, Shamima
name: Chinnery, Patrick F
name: Genomics England Research Consortium
name: Ambrose, John C
name: Arumugam, Prabhu
name: Bevers, Roel
name: Bleda, Marta
name: Boardman-Pretty, Freya
name: Boustred, Christopher R
name: Brittain, Helen
name: Caulfield, Mark J
name: Chan, Georgia C
name: Elgar, Greg
name: Fowler, Tom
name: Giess, Adam
name: Hamblin, Angela
name: Henderson, Shirley
name: Hubbard, Tim J P
name: Jackson, Rob
name: Jones, Louise J
name: Kasperaviciute, Dalia
name: Kayikci, Melis
name: Kousathanas, Athanasios
name: Lahnstein, Lea
name: Leigh, Sarah E A
name: Leong, Ivonne U S
name: Lopez, Javier F
name: Maleady-Crowe, Fiona
name: McEntegart, Meriel
name: Minneci, Federico
name: Moutsianas, Loukas
name: Mueller, Michael
name: Murugaesu, Nirupa
name: Need, Anna C
name: O’Donovan, Peter
name: Odhams, Chris A
name: Patch, Christine
name: Buonerimo Pereira, Mariana
name: Perez-Gil, Daniel
name: Pullinger, John
name: Rahim, Tahrima
name: Rendon, Augusto
name: Rogers, Tim
name: Savage, Kevin
name: Sawant, Kushmita
name: Scott, Richard H
name: Siddiq, Afshan
name: Sieghart, Alexander
name: Smith, Samuel C
name: Sosinsky, Alona
name: Stuckey, Alexander
name: Tanguy, Mélanie
name: Taylor Tavares, Ana Lisa
name: Thomas, Ellen R A
name: Thompson, Simon R
name: Welland, Matthew J
name: Williams, Eleanor
name: Witkowska, Katarzyna
name: Wood, Suzanne M
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Research

description: Funder: University of Cambridge; FundRef: http://dx.doi.org/10.13039/501100000735
description: Funder: Alzheimer's Society; FundRef: http://dx.doi.org/10.13039/501100000320
description: Funder: Leverhulme Trust; FundRef: http://dx.doi.org/10.13039/501100000275
description: Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272
description: Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276
description: Funder: Evelyn Trust; FundRef: http://dx.doi.org/10.13039/501100004282
description: Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440
description: Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265
description: Abstract: 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.