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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

ABSTRACT: To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

SUBMITTER: Taylor JC

PROVIDER: S-EPMC4601524 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

Taylor Jenny C JC Martin Hilary C HC Lise Stefano S Broxholme John J Cazier Jean-Baptiste JB Rimmer Andy A Kanapin Alexander A Lunter Gerton G Fiddy Simon S Allan Chris C Aricescu A Radu AR Attar Moustafa M Babbs Christian C Becq Jennifer J Beeson David D Bento Celeste C Bignell Patricia P Blair Edward E Buckle Veronica J VJ Bull Katherine K Cais Ondrej O Cario Holger H Chapel Helen H Copley Richard R RR Cornall Richard R Craft Jude J Dahan Karin K Davenport Emma E EE Dendrou Calliope C Devuyst Olivier O Fenwick Aimée L AL Flint Jonathan J Fugger Lars L Gilbert Rodney D RD Goriely Anne A Green Angie A Greger Ingo H IH Grocock Russell R Gruszczyk Anja V AV Hastings Robert R Hatton Edouard E Higgs Doug D Hill Adrian A Holmes Chris C Howard Malcolm M Hughes Linda L Humburg Peter P Johnson David D Karpe Fredrik F Kingsbury Zoya Z Kini Usha U Knight Julian C JC Krohn Jonathan J Lamble Sarah S Langman Craig C Lonie Lorne L Luck Joshua J McCarthy Davis D McGowan Simon J SJ McMullin Mary Frances MF Miller Kerry A KA Murray Lisa L Németh Andrea H AH Nesbit M Andrew MA Nutt David D Ormondroyd Elizabeth E Oturai Annette Bang AB Pagnamenta Alistair A Patel Smita Y SY Percy Melanie M Petousi Nayia N Piazza Paolo P Piret Sian E SE Polanco-Echeverry Guadalupe G Popitsch Niko N Powrie Fiona F Pugh Chris C Quek Lynn L Robbins Peter A PA Robson Kathryn K Russo Alexandra A Sahgal Natasha N van Schouwenburg Pauline A PA Schuh Anna A Silverman Earl E Simmons Alison A Sørensen Per Soelberg PS Sweeney Elizabeth E Taylor John J Thakker Rajesh V RV Tomlinson Ian I Trebes Amy A Twigg Stephen Rf SR Uhlig Holm H HH Vyas Paresh P Vyse Tim T Wall Steven A SA Watkins Hugh H Whyte Michael P MP Witty Lorna L Wright Ben B Yau Chris C Buck David D Humphray Sean S Ratcliffe Peter J PJ Bell John I JI Wilkie Andrew Om AO Bentley David D Donnelly Peter P McVean Gilean G

Nature genetics 20150518 7

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both ...[more]

PMID: 25985138

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Project description:Background/objectivesThe timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have?MethodsA systematic search was conducted using the following search terms (simplified): "Whole exome sequencing (WES)," "Whole genome sequencing (WGS)," "IMD," "diagnostics" and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established.ResultsThe diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD.ConclusionES and/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021295156.

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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.

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