Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Keren J. Carss; Gavin Arno; Marie Erwood; Jonathan Stephens; Alba Sanchis-Juan; Sarah Hull; Karyn Megy; Detelina Grozeva; Eleanor Dewhurst; Samantha Malka; Vincent Plagnol; Christopher Penkett; Kathleen Stirrups; Roberta Rizzo; Genevieve Wright; Dragana Josifova; Maria Bitner-Glindzicz; Richard H. Scott; Emma Clement; Louise Allen; Ruth Armstrong; Angela F. Brady; Jenny Carmichael; Manali Chitre; Robert H H Henderson; Jane Hurst; Robert E. MacLaren; Elaine Murphy; Joan Paterson; Elisabeth Rosser; Dorothy A. Thompson; Emma Wakeling; Willem H. Ouwehand; Michel Michaelides; Anthony T. Moore; Timothy Aitman; Hana Alachkar; Sonia Ali; Louise Allen; David Allsup; Gautum Ambegaonkar; Julie Anderson; Richard Antrobus; Ruth Armstrong; Gavin Arno; Gururaj Arumugakani; Sofie Ashford; William Astle; Antony Attwood; Steve Austin; Chiara Bacchelli; Tamam Bakchoul; Tadbir K. Bariana; Helen Baxendale; David Bennett; Claire Bethune; Shahnaz Bibi; Maria Bitner-Glindzicz; Marta Bleda; Harm Boggard; Paula Bolton-Maggs; Claire Booth; Angie Brady; Matthew Brown; Michael Browning; Christine Bryson; Siobhan Burns; Paul Calleja; Natalie Canham; Jenny Carmichael; Keren Carss; Mark Caulfield; Elizabeth Chalmers; Anita Chandra; Patrick Chinnery; Manali Chitre; Colin Church; Emma Clement; Naomi Clements-Brod; Virginia Clowes; Gerry Coghlan; Peter Collins; Nichola Cooper; Amanda Creaser-Myers; Rosa DaCosta; Louise Daugherty; Sophie Davies; John Davis; Minka De Vries; Patrick Deegan; Sri V V Deevi; Charu Deshpande; Lisa Devlin; Eleanor Dewhurst; Rainer Doffinger; Natalie Dormand; Elizabeth Drewe; David Edgar; William Egner; Wendy N. Erber; Marie Erwood; Tamara Everington; Remi Favier; Helen Firth; Debra Fletcher; Frances Flinter; James C. Fox; Amy Frary; Kathleen Freson; Bruce Furie; Abigail Furnell; Daniel Gale; Alice Gardham; Michael Gattens; Neeti Ghali; Pavandeep K. Ghataorhe; Rohit Ghurye; Simon Gibbs; Kimberley Gilmour; Paul Gissen; Sarah Goddard; Keith Gomez; Pavel Gordins; Stefan Gräf; Daniel Greene; Alan Greenhalgh; Andreas Greinacher; Sofia Grigoriadou; Detelina Grozeva; Scott Hackett; Charaka Hadinnapola; Rosie Hague; Matthias Haimel; Csaba Halmagyi; Tracey Hammerton; Daniel Hart; Grant Hayman; Johan W M Heemskerk; Robert Henderson; Anke Hensiek; Yvonne Henskens; Archana Herwadkar; Simon Holden; Muriel Holder; Susan Holder; Fengyuan Hu; Aarnoud Huissoon; Marc Humbert; Jane Hurst; Roger James; Stephen Jolles; Dragana Josifova; Rashid Kazmi; David Keeling; Peter Kelleher; Anne M. Kelly; Fiona Kennedy; David Kiely; Nathalie Kingston; Ania Koziell; Deepa Krishnakumar; Taco W. Kuijpers; Dinakantha Kumararatne; Manju Kurian; Michael A. Laffan; Michele P. Lambert; Hana Lango Allen; Allan Lawrie; Sara Lear; Melissa Lees; Claire Lentaigne; Ri Liesner; Rachel Linger; Hilary Longhurst; Lorena Lorenzo; Rajiv Machado; Rob Mackenzie; Robert MacLaren; Eamonn Maher; Jesmeen Maimaris; Sarah Mangles; Ania Manson; Rutendo Mapeta; Hugh S. Markus; Jennifer Martin; Larahmie Masati; Mary Mathias; Vera Matser; Anna Maw; Elizabeth McDermott; Coleen McJannet; Stuart Meacham; Sharon Meehan; Karyn Megy; Sarju Mehta; Michel Michaelides; Carolyn M. Millar; Shahin Moledina; Anthony Moore; Nicholas Morrell; Andrew Mumford; Sai Murng; Elaine Murphy; Sergey Nejentsev; Sadia Noorani; Paquita Nurden; Eric Oksenhendler; Willem H. Ouwehand; Sofia Papadia; Soo Mi Park; Alasdair Parker; John Pasi; Chris Patch; Joan Paterson; Jeanette Payne; Andrew Peacock; Kathelijne Peerlinck; Christopher J. Penkett; Joanna Pepke-Zaba; David J. Perry; Val Pollock; Gary Polwarth; Mark Ponsford; Waseem Qasim; Isabella Quinti; Stuart Rankin; Julia Rankin; F. Lucy Raymond; Karola Rehnstrom; Evan Reid; Christopher J. Rhodes; Michael Richards; Sylvia Richardson; Alex Richter; Irene Roberts; Matthew Rondina; Elisabeth Rosser; Catherine Roughley; Kevin Rue-Albrecht; Crina Samarghitean; Alba Sanchis-Juan; Richard Sandford; Saikat Santra; Ravishankar Sargur; Sinisa Savic; Sol Schulman; Harald Schulze; Richard Scott; Marie Scully; Suranjith Seneviratne; Carrock Sewell; Olga Shamardina; Debbie Shipley; Ilenia Simeoni; Suthesh Sivapalaratnam; Kenneth Smith; Aman Sohal; Laura Southgate; Simon Staines; Emily Staples; Hans Stauss; Penelope Stein; Jonathan Stephens; Kathleen Stirrups; Sophie Stock; Jay Suntharalingam; R. Campbell Tait; Kate Talks; Yvonne Tan; Jecko Thachil; James Thaventhiran; Ellen Thomas; Moira Thomas; Dorothy Thompson; Adrian Thrasher; Marc Tischkowitz; Catherine Titterton; Cheng Hock Toh; Mark Toshner; Carmen Treacy; Richard Trembath; Salih Tuna; Wojciech Turek; Ernest Turro; Chris Van Geet; Marijke Veltman; Julie Vogt; Julie von Ziegenweldt; Anton Vonk Noordegraaf; Emma Wakeling; Ivy Wanjiku; Timothy Q. Warner; Evangeline Wassmer; Hugh Watkins; Andrew Webster; Steve Welch; Sarah Westbury; John Wharton; Deborah Whitehorn; Martin Wilkins; Lisa Willcocks; Catherine Williamson; Geoffrey Woods; John Wort; Nigel Yeatman; Patrick Yong; Tim Young; Ping Yu; Andrew R. Webster; F. Lucy Raymond

doi:10.1016/j.ajhg.2016.12.003

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise AllenRuth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H H Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V V Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W M Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Soo Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, F. Lucy Raymond, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Andrew R. Webster, F. Lucy Raymond

Research output: Contribution to journal › Article › peer-review

329 Citations (Scopus)

Abstract

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Original language	English
Pages (from-to)	75-90
Number of pages	16
Journal	American Journal of Human Genetics
Volume	100
Issue number	1
Early online date	29 Dec 2016
DOIs	https://doi.org/10.1016/j.ajhg.2016.12.003
Publication status	Published - 5 Jan 2017

Keywords

copy-number variants
rare sequence variant
retinal dystrophy
whole-genome sequence

Access to Document

10.1016/j.ajhg.2016.12.003

Cite this

Carss, K. J., Arno, G., Erwood, M., Stephens, J., Sanchis-Juan, A., Hull, S., Megy, K., Grozeva, D., Dewhurst, E., Malka, S., Plagnol, V., Penkett, C., Stirrups, K., Rizzo, R., Wright, G., Josifova, D., Bitner-Glindzicz, M., Scott, R. H., Clement, E., ... Raymond, F. L. (2017). Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. American Journal of Human Genetics, 100(1), 75-90. https://doi.org/10.1016/j.ajhg.2016.12.003

@article{0354fc7bcb3b4cd2b0b00ba7290e9f74,

title = "Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease",

abstract = "Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.",

keywords = "copy-number variants, rare sequence variant, retinal dystrophy, whole-genome sequence",

author = "Carss, {Keren J.} and Gavin Arno and Marie Erwood and Jonathan Stephens and Alba Sanchis-Juan and Sarah Hull and Karyn Megy and Detelina Grozeva and Eleanor Dewhurst and Samantha Malka and Vincent Plagnol and Christopher Penkett and Kathleen Stirrups and Roberta Rizzo and Genevieve Wright and Dragana Josifova and Maria Bitner-Glindzicz and Scott, {Richard H.} and Emma Clement and Louise Allen and Ruth Armstrong and Brady, {Angela F.} and Jenny Carmichael and Manali Chitre and Henderson, {Robert H H} and Jane Hurst and MacLaren, {Robert E.} and Elaine Murphy and Joan Paterson and Elisabeth Rosser and Thompson, {Dorothy A.} and Emma Wakeling and Ouwehand, {Willem H.} and Michel Michaelides and Moore, {Anthony T.} and Timothy Aitman and Hana Alachkar and Sonia Ali and Louise Allen and David Allsup and Gautum Ambegaonkar and Julie Anderson and Richard Antrobus and Ruth Armstrong and Gavin Arno and Gururaj Arumugakani and Sofie Ashford and William Astle and Antony Attwood and Steve Austin and Chiara Bacchelli and Tamam Bakchoul and Bariana, {Tadbir K.} and Helen Baxendale and David Bennett and Claire Bethune and Shahnaz Bibi and Maria Bitner-Glindzicz and Marta Bleda and Harm Boggard and Paula Bolton-Maggs and Claire Booth and Angie Brady and Matthew Brown and Michael Browning and Christine Bryson and Siobhan Burns and Paul Calleja and Natalie Canham and Jenny Carmichael and Keren Carss and Mark Caulfield and Elizabeth Chalmers and Anita Chandra and Patrick Chinnery and Manali Chitre and Colin Church and Emma Clement and Naomi Clements-Brod and Virginia Clowes and Gerry Coghlan and Peter Collins and Nichola Cooper and Amanda Creaser-Myers and Rosa DaCosta and Louise Daugherty and Sophie Davies and John Davis and {De Vries}, Minka and Patrick Deegan and Deevi, {Sri V V} and Charu Deshpande and Lisa Devlin and Eleanor Dewhurst and Rainer Doffinger and Natalie Dormand and Elizabeth Drewe and David Edgar and William Egner and Erber, {Wendy N.} and Marie Erwood and Tamara Everington and Remi Favier and Helen Firth and Debra Fletcher and Frances Flinter and Fox, {James C.} and Amy Frary and Kathleen Freson and Bruce Furie and Abigail Furnell and Daniel Gale and Alice Gardham and Michael Gattens and Neeti Ghali and Ghataorhe, {Pavandeep K.} and Rohit Ghurye and Simon Gibbs and Kimberley Gilmour and Paul Gissen and Sarah Goddard and Keith Gomez and Pavel Gordins and Stefan Gr{\"a}f and Daniel Greene and Alan Greenhalgh and Andreas Greinacher and Sofia Grigoriadou and Detelina Grozeva and Scott Hackett and Charaka Hadinnapola and Rosie Hague and Matthias Haimel and Csaba Halmagyi and Tracey Hammerton and Daniel Hart and Grant Hayman and Heemskerk, {Johan W M} and Robert Henderson and Anke Hensiek and Yvonne Henskens and Archana Herwadkar and Simon Holden and Muriel Holder and Susan Holder and Fengyuan Hu and Aarnoud Huissoon and Marc Humbert and Jane Hurst and Roger James and Stephen Jolles and Dragana Josifova and Rashid Kazmi and David Keeling and Peter Kelleher and Kelly, {Anne M.} and Fiona Kennedy and David Kiely and Nathalie Kingston and Ania Koziell and Deepa Krishnakumar and Kuijpers, {Taco W.} and Dinakantha Kumararatne and Manju Kurian and Laffan, {Michael A.} and Lambert, {Michele P.} and Allen, {Hana Lango} and Allan Lawrie and Sara Lear and Melissa Lees and Claire Lentaigne and Ri Liesner and Rachel Linger and Hilary Longhurst and Lorena Lorenzo and Rajiv Machado and Rob Mackenzie and Robert MacLaren and Eamonn Maher and Jesmeen Maimaris and Sarah Mangles and Ania Manson and Rutendo Mapeta and Markus, {Hugh S.} and Jennifer Martin and Larahmie Masati and Mary Mathias and Vera Matser and Anna Maw and Elizabeth McDermott and Coleen McJannet and Stuart Meacham and Sharon Meehan and Karyn Megy and Sarju Mehta and Michel Michaelides and Millar, {Carolyn M.} and Shahin Moledina and Anthony Moore and Nicholas Morrell and Andrew Mumford and Sai Murng and Elaine Murphy and Sergey Nejentsev and Sadia Noorani and Paquita Nurden and Eric Oksenhendler and Ouwehand, {Willem H.} and Sofia Papadia and Park, {Soo Mi} and Alasdair Parker and John Pasi and Chris Patch and Joan Paterson and Jeanette Payne and Andrew Peacock and Kathelijne Peerlinck and Penkett, {Christopher J.} and Joanna Pepke-Zaba and Perry, {David J.} and Val Pollock and Gary Polwarth and Mark Ponsford and Waseem Qasim and Isabella Quinti and Stuart Rankin and Julia Rankin and Raymond, {F. Lucy} and Karola Rehnstrom and Evan Reid and Rhodes, {Christopher J.} and Michael Richards and Sylvia Richardson and Alex Richter and Irene Roberts and Matthew Rondina and Elisabeth Rosser and Catherine Roughley and Kevin Rue-Albrecht and Crina Samarghitean and Alba Sanchis-Juan and Richard Sandford and Saikat Santra and Ravishankar Sargur and Sinisa Savic and Sol Schulman and Harald Schulze and Richard Scott and Marie Scully and Suranjith Seneviratne and Carrock Sewell and Olga Shamardina and Debbie Shipley and Ilenia Simeoni and Suthesh Sivapalaratnam and Kenneth Smith and Aman Sohal and Laura Southgate and Simon Staines and Emily Staples and Hans Stauss and Penelope Stein and Jonathan Stephens and Kathleen Stirrups and Sophie Stock and Jay Suntharalingam and Tait, {R. Campbell} and Kate Talks and Yvonne Tan and Jecko Thachil and James Thaventhiran and Ellen Thomas and Moira Thomas and Dorothy Thompson and Adrian Thrasher and Marc Tischkowitz and Catherine Titterton and Toh, {Cheng Hock} and Mark Toshner and Carmen Treacy and Richard Trembath and Salih Tuna and Wojciech Turek and Ernest Turro and {Van Geet}, Chris and Marijke Veltman and Julie Vogt and {von Ziegenweldt}, Julie and Noordegraaf, {Anton Vonk} and Emma Wakeling and Ivy Wanjiku and Warner, {Timothy Q.} and Evangeline Wassmer and Hugh Watkins and Andrew Webster and Steve Welch and Sarah Westbury and John Wharton and Deborah Whitehorn and Martin Wilkins and Lisa Willcocks and Catherine Williamson and Geoffrey Woods and John Wort and Nigel Yeatman and Patrick Yong and Tim Young and Ping Yu and Webster, {Andrew R.} and Raymond, {F. Lucy}",

year = "2017",

month = jan,

day = "5",

doi = "10.1016/j.ajhg.2016.12.003",

language = "English",

volume = "100",

pages = "75--90",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "1",

}

Carss, KJ, Arno, G, Erwood, M, Stephens, J, Sanchis-Juan, A, Hull, S, Megy, K, Grozeva, D, Dewhurst, E, Malka, S, Plagnol, V, Penkett, C, Stirrups, K, Rizzo, R, Wright, G, Josifova, D, Bitner-Glindzicz, M, Scott, RH, Clement, E, Allen, L, Armstrong, R, Brady, AF, Carmichael, J, Chitre, M, Henderson, RHH, Hurst, J, MacLaren, RE, Murphy, E, Paterson, J, Rosser, E, Thompson, DA, Wakeling, E, Ouwehand, WH, Michaelides, M, Moore, AT, Aitman, T, Alachkar, H, Ali, S, Allen, L, Allsup, D, Ambegaonkar, G, Anderson, J, Antrobus, R, Armstrong, R, Arno, G, Arumugakani, G, Ashford, S, Astle, W, Attwood, A, Austin, S, Bacchelli, C, Bakchoul, T, Bariana, TK, Baxendale, H, Bennett, D, Bethune, C, Bibi, S, Bitner-Glindzicz, M, Bleda, M, Boggard, H, Bolton-Maggs, P, Booth, C, Brady, A, Brown, M, Browning, M, Bryson, C, Burns, S, Calleja, P, Canham, N, Carmichael, J, Carss, K, Caulfield, M, Chalmers, E, Chandra, A, Chinnery, P, Chitre, M, Church, C, Clement, E, Clements-Brod, N, Clowes, V, Coghlan, G, Collins, P, Cooper, N, Creaser-Myers, A, DaCosta, R, Daugherty, L, Davies, S, Davis, J, De Vries, M, Deegan, P, Deevi, SVV, Deshpande, C, Devlin, L, Dewhurst, E, Doffinger, R, Dormand, N, Drewe, E, Edgar, D, Egner, W, Erber, WN, Erwood, M, Everington, T, Favier, R, Firth, H, Fletcher, D, Flinter, F, Fox, JC, Frary, A, Freson, K, Furie, B, Furnell, A, Gale, D, Gardham, A, Gattens, M, Ghali, N, Ghataorhe, PK, Ghurye, R, Gibbs, S, Gilmour, K, Gissen, P, Goddard, S, Gomez, K, Gordins, P, Gräf, S, Greene, D, Greenhalgh, A, Greinacher, A, Grigoriadou, S, Grozeva, D, Hackett, S, Hadinnapola, C, Hague, R, Haimel, M, Halmagyi, C, Hammerton, T, Hart, D, Hayman, G, Heemskerk, JWM, Henderson, R, Hensiek, A, Henskens, Y, Herwadkar, A, Holden, S, Holder, M, Holder, S, Hu, F, Huissoon, A, Humbert, M, Hurst, J, James, R, Jolles, S, Josifova, D, Kazmi, R, Keeling, D, Kelleher, P, Kelly, AM, Kennedy, F, Kiely, D, Kingston, N, Koziell, A, Krishnakumar, D, Kuijpers, TW, Kumararatne, D, Kurian, M, Laffan, MA, Lambert, MP, Allen, HL, Lawrie, A, Lear, S, Lees, M, Lentaigne, C, Liesner, R, Linger, R, Longhurst, H, Lorenzo, L, Machado, R, Mackenzie, R, MacLaren, R, Maher, E, Maimaris, J, Mangles, S, Manson, A, Mapeta, R, Markus, HS, Martin, J, Masati, L, Mathias, M, Matser, V, Maw, A, McDermott, E, McJannet, C, Meacham, S, Meehan, S, Megy, K, Mehta, S, Michaelides, M, Millar, CM, Moledina, S, Moore, A, Morrell, N, Mumford, A, Murng, S, Murphy, E, Nejentsev, S, Noorani, S, Nurden, P, Oksenhendler, E, Ouwehand, WH, Papadia, S, Park, SM, Parker, A, Pasi, J, Patch, C, Paterson, J, Payne, J, Peacock, A, Peerlinck, K, Penkett, CJ, Pepke-Zaba, J, Perry, DJ, Pollock, V, Polwarth, G, Ponsford, M, Qasim, W, Quinti, I, Rankin, S, Rankin, J, Raymond, FL, Rehnstrom, K, Reid, E, Rhodes, CJ, Richards, M, Richardson, S, Richter, A, Roberts, I, Rondina, M, Rosser, E, Roughley, C, Rue-Albrecht, K, Samarghitean, C, Sanchis-Juan, A, Sandford, R, Santra, S, Sargur, R, Savic, S, Schulman, S, Schulze, H, Scott, R, Scully, M, Seneviratne, S, Sewell, C, Shamardina, O, Shipley, D, Simeoni, I, Sivapalaratnam, S, Smith, K, Sohal, A, Southgate, L, Staines, S, Staples, E, Stauss, H, Stein, P, Stephens, J, Stirrups, K, Stock, S, Suntharalingam, J, Tait, RC, Talks, K, Tan, Y, Thachil, J, Thaventhiran, J, Thomas, E, Thomas, M, Thompson, D, Thrasher, A, Tischkowitz, M, Titterton, C, Toh, CH, Toshner, M, Treacy, C, Trembath, R, Tuna, S, Turek, W, Turro, E, Van Geet, C, Veltman, M, Vogt, J, von Ziegenweldt, J, Noordegraaf, AV, Wakeling, E, Wanjiku, I, Warner, TQ, Wassmer, E, Watkins, H, Webster, A, Welch, S, Westbury, S, Wharton, J, Whitehorn, D, Wilkins, M, Willcocks, L, Williamson, C, Woods, G, Wort, J, Yeatman, N, Yong, P, Young, T, Yu, P, Webster, AR & Raymond, FL 2017, 'Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease', American Journal of Human Genetics, vol. 100, no. 1, pp. 75-90. https://doi.org/10.1016/j.ajhg.2016.12.003

TY - JOUR

T1 - Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

AU - Carss, Keren J.

AU - Arno, Gavin

AU - Erwood, Marie

AU - Stephens, Jonathan

AU - Sanchis-Juan, Alba

AU - Hull, Sarah

AU - Megy, Karyn

AU - Grozeva, Detelina

AU - Dewhurst, Eleanor

AU - Malka, Samantha

AU - Plagnol, Vincent

AU - Penkett, Christopher

AU - Stirrups, Kathleen

AU - Rizzo, Roberta

AU - Wright, Genevieve

AU - Josifova, Dragana

AU - Bitner-Glindzicz, Maria

AU - Scott, Richard H.

AU - Clement, Emma

AU - Allen, Louise

AU - Armstrong, Ruth

AU - Brady, Angela F.

AU - Carmichael, Jenny

AU - Chitre, Manali

AU - Henderson, Robert H H

AU - Hurst, Jane

AU - MacLaren, Robert E.

AU - Murphy, Elaine

AU - Paterson, Joan

AU - Rosser, Elisabeth

AU - Thompson, Dorothy A.

AU - Wakeling, Emma

AU - Ouwehand, Willem H.

AU - Michaelides, Michel

AU - Moore, Anthony T.

AU - Aitman, Timothy

AU - Alachkar, Hana

AU - Ali, Sonia

AU - Allen, Louise

AU - Allsup, David

AU - Ambegaonkar, Gautum

AU - Anderson, Julie

AU - Antrobus, Richard

AU - Armstrong, Ruth

AU - Arno, Gavin

AU - Arumugakani, Gururaj

AU - Ashford, Sofie

AU - Astle, William

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AU - Raymond, F. Lucy

PY - 2017/1/5

Y1 - 2017/1/5

N2 - Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

AB - Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

KW - copy-number variants

KW - rare sequence variant

KW - retinal dystrophy

KW - whole-genome sequence

UR - http://www.scopus.com/inward/record.url?scp=85009380953&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.12.003

DO - 10.1016/j.ajhg.2016.12.003

M3 - Article

AN - SCOPUS:85009380953

SN - 0002-9297

VL - 100

SP - 75

EP - 90

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

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