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 | |
| Publication status | Published - Jul 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
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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. / Taylor, Jenny C; Martin, Hilary C; Lise, Stefano; Broxholme, John; Cazier, Jean-Baptiste; Rimmer, Andy; Kanapin, Alexander; Lunter, Gerton; Fiddy, Simon; Allan, Chris; Aricescu, A Radu; Attar, Moustafa; Babbs, Christian; Becq, Jennifer; Beeson, David; Bento, Celeste; Bignell, Patricia; Blair, Edward; Buckle, Veronica J; Bull, Katherine; Cais, Ondrej; Cario, Holger; Chapel, Helen; Copley, Richard R; Cornall, Richard; Craft, Jude; Dahan, Karin; Davenport, Emma E; Dendrou, Calliope; Devuyst, Olivier; Fenwick, Aimée L; Flint, Jonathan; Fugger, Lars; Gilbert, Rodney D; Goriely, Anne; Green, Angie; Greger, Ingo H; Grocock, Russell; Gruszczyk, Anja V; Hastings, Robert; Hatton, Edouard; Higgs, Doug; Hill, Adrian; Holmes, Chris; Howard, Malcolm; Hughes, Linda; Humburg, Peter; Johnson, David; Karpe, Fredrik; Kingsbury, Zoya; Kini, Usha; Knight, Julian C; Krohn, Jonathan; Lamble, Sarah; Langman, Craig; Lonie, Lorne; Luck, Joshua; McCarthy, Davis; McGowan, Simon J; McMullin, Mary Frances; Miller, Kerry A; Murray, Lisa; Németh, Andrea H; Nesbit, M Andrew; Nutt, David; Ormondroyd, Elizabeth; Oturai, Annette Bang; Pagnamenta, Alistair; Patel, Smita Y; Percy, Melanie; Petousi, Nayia; Piazza, Paolo; Piret, Sian E; Polanco-Echeverry, Guadalupe; Popitsch, Niko; Powrie, Fiona; Pugh, Chris; Quek, Lynn; Robbins, Peter A; Robson, Kathryn; Russo, Alexandra; Sahgal, Natasha; van Schouwenburg, Pauline A; Schuh, Anna; Silverman, Earl; Simmons, Alison; Sørensen, Per Soelberg; Sweeney, Elizabeth; Taylor, John; Thakker, Rajesh V; Tomlinson, Ian; Trebes, Amy; Twigg, Stephen R F; Uhlig, Holm H; Vyas, Paresh; Vyse, Tim; Wall, Steven A; Watkins, Hugh; Whyte, Michael P; Witty, Lorna; Wright, Ben; Yau, Chris; Buck, David; Humphray, Sean; Ratcliffe, Peter J; Bell, John I; Wilkie, Andrew O M; Bentley, David; Donnelly, Peter; McVean, Gilean.
In: Nature Genetics, Vol. 47, No. 7, 07.2015, p. 717-26.Research output: Contribution to journal › Journal article › Research › peer-review
}
TY - JOUR
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 - 2015/7
Y1 - 2015/7
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
VL - 47
SP - 717
EP - 726
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 7
ER -