Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. (3rd November 2021)

• Record Type: Journal Article
• Authors: Schon, Katherine R; Horvath, Rita; Wei, Wei; Calabrese, Claudia; Tucci, Arianna; Ibañez, Kristina; Ratnaike, Thiloka; Pitceathly, Robert D S; Bugiardini, Enrico; Quinlivan, Rosaline; Hanna, Michael G; Clement, Emma; Ashton, Emma; Sayer, John A; Brennan, Paul; Josifova, Dragana; Izatt, Louise; Fratter, Carl; Nesbitt, Victoria; Barrett, Timothy; McMullen, Dominic J; Smith, Audrey; Deshpande, Charulata; Smithson, Sarah F; Festenstein, Richard; Canham, Natalie; Caulfield, Mark; Houlden, Henry; Rahman(, Shamima; Chinnery, Patrick F
• Other Names: author non-byline.; Ambrose John C author non-byline.; Arumugam Prabhu author non-byline.; Bevers Roel author non-byline.; Bleda Marta author non-byline.; Boardman-Pretty Freya author non-byline.; Boustred Christopher R author non-byline.; Brittain Helen author non-byline.; Caulfield Mark J author non-byline.; Chan Georgia C author non-byline.; Elgar Greg author non-byline.; Fowler Tom author non-byline.; Giess Adam author non-byline.; Hamblin Angela author non-byline.; Henderson Shirley author non-byline.; Hubbard Tim J P author non-byline.; Jackson Rob author non-byline.; Jones Louise J author non-byline.; Kasperaviciute Dalia author non-byline.; Kayikci Melis author non-byline.; Kousathanas Athanasios author non-byline.; Lahnstein Lea author non-byline.; Leigh Sarah E A author non-byline.; Leong Ivonne U S author non-byline.; Lopez Javier F author non-byline.; Maleady-Crowe Fiona author non-byline.; McEntegart Meriel author non-byline.; Minneci Federico author non-byline.; Moutsianas Loukas author non-byline.; Mueller Michael author non-byline.; Murugaesu Nirupa author non-byline.; Need Anna C author non-byline.; O'Donovan Peter author non-byline.; Odhams Chris A author non-byline.; Patch Christine author non-byline.; Buonerimo Pereira Mariana author non-byline.; Perez-Gil Daniel author non-byline.; Pullinger John author non-byline.; Rahim Tahrima author non-byline.; Rendon Augusto author non-byline.; Rogers Tim author non-byline.; Savage Kevin author non-byline.; Sawant Kushmita author non-byline.; Scott Richard H author non-byline.; Siddiq Afshan author non-byline.; Sieghart Alexander author non-byline.; Smith Samuel C author non-byline.; Sosinsky Alona author non-byline.; Stuckey Alexander author non-byline.; Tanguy Mélanie author non-byline.; Taylor Tavares Ana Lisa author non-byline.; Thomas Ellen R A author non-byline.; Thompson Simon R author non-byline.; Tucci Arianna author non-byline.; Welland Matthew J author non-byline.; Williams Eleanor author non-byline.; Witkowska Katarzyna author non-byline.; Wood Suzanne M author non-byline.;
• Is Part Of: BMJ. Volume 375(2021)
• Publication Date: 2021-11-03
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Periodicals; 610
• DOI: 10.1136/bmj-2021-066288
• Languages: English
• ISSNs: 0007-1447

Abstract

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.