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

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

doi:10.1038/ng.3304

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

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

Department of Clinical Medicine

195 Citations (Scopus)

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.

Original language	English
Journal	Nature Genetics
Volume	47
Issue number	7
Pages (from-to)	717-26
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3304
Publication status	Published - 26 Jun 2015

Keywords

Base Sequence
DNA Mutational Analysis
Genetic Diseases, Inborn
Genome, Human
High-Throughput Nucleotide Sequencing
Humans
Molecular Diagnostic Techniques
Molecular Sequence Annotation
Polymorphism, Single Nucleotide
Sensitivity and Specificity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3304

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Taylor, J. C., Martin, H. C., Lise, S., Broxholme, J., Cazier, J-B., Rimmer, A., Kanapin, A., Lunter, G., Fiddy, S., Allan, C., Aricescu, A. R., Attar, M., Babbs, C., Becq, J., Beeson, D., Bento, C., Bignell, P., Blair, E., Buckle, V. J., ... McVean, G. (2015). Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nature Genetics, 47(7), 717-26. https://doi.org/10.1038/ng.3304

Taylor, JC, Martin, HC, Lise, S, Broxholme, J, Cazier, J-B, Rimmer, A, Kanapin, A, Lunter, G, Fiddy, S, Allan, C, Aricescu, AR, Attar, M, Babbs, C, Becq, J, Beeson, D, Bento, C, Bignell, P, Blair, E, Buckle, VJ, Bull, K, Cais, O, Cario, H, Chapel, H, Copley, RR, Cornall, R, Craft, J, Dahan, K, Davenport, EE, Dendrou, C, Devuyst, O, Fenwick, AL, Flint, J, Fugger, L, Gilbert, RD, Goriely, A, Green, A, Greger, IH, Grocock, R, Gruszczyk, AV, Hastings, R, Hatton, E, Higgs, D, Hill, A, Holmes, C, Howard, M, Hughes, L, Humburg, P, Johnson, D, Karpe, F, Kingsbury, Z, Kini, U, Knight, JC, Krohn, J, Lamble, S, Langman, C, Lonie, L, Luck, J, McCarthy, D, McGowan, SJ, McMullin, MF, Miller, KA, Murray, L, Németh, AH, Nesbit, MA, Nutt, D, Ormondroyd, E, Oturai, AB, Pagnamenta, A, Patel, SY, Percy, M, Petousi, N, Piazza, P, Piret, SE, Polanco-Echeverry, G, Popitsch, N, Powrie, F, Pugh, C, Quek, L, Robbins, PA, Robson, K, Russo, A, Sahgal, N, van Schouwenburg, PA, Schuh, A, Silverman, E, Simmons, A, Sørensen, PS, Sweeney, E, Taylor, J, Thakker, RV, Tomlinson, I, Trebes, A, Twigg, SRF, Uhlig, HH, Vyas, P, Vyse, T, Wall, SA, Watkins, H, Whyte, MP, Witty, L, Wright, B, Yau, C, Buck, D, Humphray, S, Ratcliffe, PJ, Bell, JI, Wilkie, AOM, Bentley, D, Donnelly, P & McVean, G 2015, 'Factors influencing success of clinical genome sequencing across a broad spectrum of disorders', Nature Genetics, vol. 47, no. 7, pp. 717-26. https://doi.org/10.1038/ng.3304

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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.",

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T1 - Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

AU - Taylor, Jenny C

AU - Martin, Hilary C

AU - Lise, Stefano

AU - Broxholme, John

AU - Cazier, Jean-Baptiste

AU - Rimmer, Andy

AU - Kanapin, Alexander

AU - Lunter, Gerton

AU - Fiddy, Simon

AU - Allan, Chris

AU - Aricescu, A Radu

AU - Attar, Moustafa

AU - Babbs, Christian

AU - Becq, Jennifer

AU - Beeson, David

AU - Bento, Celeste

AU - Bignell, Patricia

AU - Blair, Edward

AU - Buckle, Veronica J

AU - Bull, Katherine

AU - Cais, Ondrej

AU - Cario, Holger

AU - Chapel, Helen

AU - Copley, Richard R

AU - Cornall, Richard

AU - Craft, Jude

AU - Dahan, Karin

AU - Davenport, Emma E

AU - Dendrou, Calliope

AU - Devuyst, Olivier

AU - Fenwick, Aimée L

AU - Flint, Jonathan

AU - Fugger, Lars

AU - Gilbert, Rodney D

AU - Goriely, Anne

AU - Green, Angie

AU - Greger, Ingo H

AU - Grocock, Russell

AU - Gruszczyk, Anja V

AU - Hastings, Robert

AU - Hatton, Edouard

AU - Higgs, Doug

AU - Hill, Adrian

AU - Holmes, Chris

AU - Howard, Malcolm

AU - Hughes, Linda

AU - Humburg, Peter

AU - Johnson, David

AU - Karpe, Fredrik

AU - Kingsbury, Zoya

AU - Kini, Usha

AU - Knight, Julian C

AU - Krohn, Jonathan

AU - Lamble, Sarah

AU - Langman, Craig

AU - Lonie, Lorne

AU - Luck, Joshua

AU - McCarthy, Davis

AU - McGowan, Simon J

AU - McMullin, Mary Frances

AU - Miller, Kerry A

AU - Murray, Lisa

AU - Németh, Andrea H

AU - Nesbit, M Andrew

AU - Nutt, David

AU - Ormondroyd, Elizabeth

AU - Oturai, Annette Bang

AU - Pagnamenta, Alistair

AU - Patel, Smita Y

AU - Percy, Melanie

AU - Petousi, Nayia

AU - Piazza, Paolo

AU - Piret, Sian E

AU - Polanco-Echeverry, Guadalupe

AU - Popitsch, Niko

AU - Powrie, Fiona

AU - Pugh, Chris

AU - Quek, Lynn

AU - Robbins, Peter A

AU - Robson, Kathryn

AU - Russo, Alexandra

AU - Sahgal, Natasha

AU - van Schouwenburg, Pauline A

AU - Schuh, Anna

AU - Silverman, Earl

AU - Simmons, Alison

AU - Sørensen, Per Soelberg

AU - Sweeney, Elizabeth

AU - Taylor, John

AU - Thakker, Rajesh V

AU - Tomlinson, Ian

AU - Trebes, Amy

AU - Twigg, Stephen R F

AU - Uhlig, Holm H

AU - Vyas, Paresh

AU - Vyse, Tim

AU - Wall, Steven A

AU - Watkins, Hugh

AU - Whyte, Michael P

AU - Witty, Lorna

AU - Wright, Ben

AU - Yau, Chris

AU - Buck, David

AU - Humphray, Sean

AU - Ratcliffe, Peter J

AU - Bell, John I

AU - Wilkie, Andrew O M

AU - Bentley, David

AU - Donnelly, Peter

AU - McVean, Gilean

PY - 2015/6/26

Y1 - 2015/6/26

N2 - 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.

AB - 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.

KW - Base Sequence

KW - DNA Mutational Analysis

KW - Genetic Diseases, Inborn

KW - Genome, Human

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Molecular Diagnostic Techniques

KW - Molecular Sequence Annotation

KW - Polymorphism, Single Nucleotide

KW - Sensitivity and Specificity

U2 - 10.1038/ng.3304

DO - 10.1038/ng.3304

M3 - Journal article

C2 - 25985138

SN - 1061-4036

VL - 47

SP - 717

EP - 726

JO - Nature: New biology

JF - Nature: New biology

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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