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

被引：275

作者：

Taylor, Jenny C. ^{[1
,2
]}

Martin, Hilary C. ^{[2
]}

Lise, Stefano ^{[2
]}

Broxholme, John ^{[2
]}

Cazier, Jean-Baptiste ^{[3
]}

Rimmer, Andy ^{[2
]}

Kanapin, Alexander ^{[2
]}

Lunter, Gerton ^{[2
]}

Fiddy, Simon ^{[2
]}

Allan, Chris ^{[2
]}

Aricescu, A. Radu ^{[2
]}

Attar, Moustafa ^{[2
]}

Babbs, Christian ^{[4
]}

Becq, Jennifer ^{[5
]}

Beeson, David ^{[6
]}

Bento, Celeste ^{[7
,8
]}

Bignell, Patricia ^{[9
]}

Blair, Edward ^{[10
]}

Buckle, Veronica J. ^{[4
]}

Bull, Katherine ^{[2
,11
]}

Cais, Ondrej ^{[12
]}

Cario, Holger ^{[13
]}

Chapel, Helen ^{[14
]}

Copley, Richard R. ^{[1
,2
]}

Cornall, Richard ^{[11
]}

Craft, Jude ^{[1
,2
]}

Dahan, Karin ^{[15
,16
]}

Davenport, Emma E. ^{[2
]}

Dendrou, Calliope ^{[17
]}

Devuyst, Olivier ^{[17
,18
]}

Fenwick, Aimee L. ^{[19
]}

Flint, Jonathan ^{[2
]}

Fugger, Lars ^{[17
]}

Gilbert, Rodney D. ^{[20
]}

Goriely, Anne ^{[19
]}

Green, Angie ^{[2
]}

Greger, Ingo H. ^{[12
]}

Grocock, Russell ^{[5
]}

Gruszczyk, Anja V. ^{[19
]}

Hastings, Robert ^{[21
]}

Hatton, Edouard ^{[2
]}

Higgs, Doug ^{[4
]}

Hill, Adrian ^{[2
,22
]}

Holmes, Chris ^{[2
,23
]}

Howard, Malcolm ^{[1
,2
]}

Hughes, Linda ^{[2
]}

Humburg, Peter ^{[2
]}

Johnson, David ^{[24
]}

Karpe, Fredrik ^{[25
]}

Kingsbury, Zoya ^{[5
]}

机构：

[1] Comprehens Biomed Res Ctr, NIHR, Oxford, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Birmingham, Ctr Computat Biol, Edgbaston, England

[4] Univ Oxford, Weatherall Inst Mol Med, Mol Haematol Unit, MRC, Oxford, England

[5] Illumina Cambridge Ltd, Saffron Walden, Essex, England

[6] Univ Oxford, Weatherall Inst Mol Med, Neurosci Grp, Oxford, England

[7] Ctr Hosp, Dept Hematol, Coimbra, Portugal

[8] Univ Coimbra, Coimbra, Portugal

[9] Oxford Univ Hosp, Natl Hlth Serv, Mol Haematol Dept, Oxford, England

[10] Univ Oxford, Hosp NHS Trust, Dept Clin Genet, Oxford, England

[11] Univ Oxford, Ctr Cellular & Mol Physiol, Oxford, England

[12] MRC, Mol Biol Lab, Div Neurobiol, Cambridge CB2 2QH, England

[13] Univ Med Ctr, Dept Pediat & Adolescent Med, Ulm, Germany

[14] Univ Oxford, Nuffield Dept Med, Primary Immunodeficiency Unit, Oxford, England

[15] Ctr Genet Humaine, Inst Genet & Pathol, Gosselies, Belgium

[16] Catholic Univ Louvain, Clin Univ St Luc, B-1200 Brussels, Belgium

[17] Univ Oxford, MRC, Weatherall Inst Mol Med, Human Immunol Unit, Oxford, England

[18] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland

[19] Univ Oxford, Weatherall Inst Mol Med, Clin Genet Grp, Oxford, England

[20] Univ Southampton, Southampton Univ Hosp, NHS Fdn Trust, Southampton, Hants, England

[21] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England

[22] Univ Oxford, Nuffield Dept Med, Jenner Inst, Oxford, England

[23] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[24] Univ Oxford, Hosp NHS Trust, Dept Plast & Reconstruct Surg, Craniofacial Unit, Oxford OX1 3TG, England

[25] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford Lab Integrat Physiol, Oxford OX1 3TG, England

[26] Northwestern Univ, Feinberg Sch Med, Kidney Dis, Chicago, IL 60611 USA

[27] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA

[28] Queens Univ, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland

[29] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

[30] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Acad Endocrine Unit, Oxford, England

[31] Univ London Imperial Coll Sci Technol & Med, Div Brain Sci, Ctr Neuropsychopharmacol, London, England

[32] Copenhagen Univ Hosp, Dept Neurol, Danish Multiple Sclerosis Ctr, Copenhagen, Denmark

[33] Belfast City Hosp, Dept Haematol, Belfast BT9 7AD, Antrim, North Ireland

[34] Univ Oxford, Nuffield Dept Med, Oxford, England

[35] Univ Oxford, Translat Gastroenterol Unit, Oxford, England

[36] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[37] Univ Hosp, Dept Pediat, Mainz, Germany

[38] Univ Oxford, Dept Oncol, Oxford, England

[39] Hosp Sick Children, Div Rheumatol, Toronto, ON M5G 1X8, Canada

[40] Liverpool Womens NHS Fdn Trust, Dept Clin Genet, Liverpool, Merseyside, England

[41] Univ Oxford, Hosp NHS Trust, Oxford NHS Reg Mol Genet Lab, Oxford, England

[42] Kings Coll London, Guys Hosp, Div Genet, London, England

[43] Shriners Hosp Children, Ctr Metab Bone Dis & Mol Res, St Louis, MO USA

[44] Univ Oxford, Off Regius Prof Med, Oxford, England

来源：

NATURE GENETICS | 2015年 / 47卷 / 07期

基金：

欧洲研究理事会; 英国医学研究理事会; 英国生物技术与生命科学研究理事会; 瑞士国家科学基金会; 英国惠康基金;

关键词：

LONG-QT SYNDROME; GERMLINE MUTATIONS; HEREDITARY BREAST; CANCER-RISKS; EXOME; VARIANTS; BRCA1; DIAGNOSIS; GENES; PREDISPOSITION;

D O I：

10.1038/ng.3304

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：717 / +

页数：13

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