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 Rf 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 Om Wilkie, David Bentley, Peter Donnelly, Gilean McVean, 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 Rf 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 Om Wilkie, David Bentley, Peter Donnelly, Gilean McVean
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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References
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