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

NIHR-BioResource Rare Diseases Consortium

Research output: Contribution to journalArticle

67 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 languageEnglish
Pages (from-to)75-90
Number of pages16
JournalAmerican Journal of Human Genetics
Volume100
Issue number1
DOIs
Publication statusPublished - 5 Jan 2017

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Retinal Diseases
Molecular Pathology
Exome
Genome
Choroideremia
GC Rich Sequence
Nucleic Acid Regulatory Sequences
Vision Disorders
Rare Diseases
Nucleotides
Research
Genes
Proteins

Cite this

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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 Penkett, {Christopher J.} and Kathleen Stirrups and Roberta Rizzo and Genevieve Wright and Dragana Josifova and Maria Bitner-Glindzicz and Richard Scott 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 Robert MacLaren and Elaine Murphy and Joan Paterson and Elisabeth Rosser and Thompson, {Dorothy A.} and Emma Wakeling and Ouwehand, {Willem H.} and Michel Michaelides and Anthony Moore 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 Bradley, {John R.} 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 {NIHR-BioResource Rare Diseases Consortium}",
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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. / NIHR-BioResource Rare Diseases Consortium.

In: American Journal of Human Genetics, Vol. 100, No. 1, 05.01.2017, p. 75-90.

Research output: Contribution to journalArticle

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 J.

AU - Stirrups, Kathleen

AU - Rizzo, Roberta

AU - Wright, Genevieve

AU - Josifova, Dragana

AU - Bitner-Glindzicz, Maria

AU - Scott, Richard

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

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

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

AU - Attwood, Antony

AU - Austin, Steve

AU - Bacchelli, Chiara

AU - Bakchoul, Tamam

AU - Bariana, Tadbir K.

AU - Baxendale, Helen

AU - Bennett, David

AU - Bethune, Claire

AU - Bibi, Shahnaz

AU - Bitner-Glindzicz, Maria

AU - Bleda, Marta

AU - Boggard, Harm

AU - Bolton-Maggs, Paula

AU - Booth, Claire

AU - Bradley, John R.

AU - Brady, Angie

AU - Brown, Matthew

AU - Browning, Michael

AU - Bryson, Christine

AU - Burns, Siobhan

AU - Calleja, Paul

AU - Canham, Natalie

AU - Carmichael, Jenny

AU - Carss, Keren

AU - Caulfield, Mark

AU - Chalmers, Elizabeth

AU - Chandra, Anita

AU - Chinnery, Patrick

AU - Chitre, Manali

AU - Church, Colin

AU - Clement, Emma

AU - Clements-Brod, Naomi

AU - Clowes, Virginia

AU - Coghlan, Gerry

AU - Collins, Peter

AU - Cooper, Nichola

AU - Creaser-Myers, Amanda

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AU - Daugherty, Louise

AU - Davies, Sophie

AU - Davis, John

AU - De Vries, Minka

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AU - Deevi, Sri V.V.

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AU - Freson, Kathleen

AU - Furie, Bruce

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AU - Ghali, Neeti

AU - Ghataorhe, Pavandeep K.

AU - Ghurye, Rohit

AU - Gibbs, Simon

AU - Gilmour, Kimberley

AU - Gissen, Paul

AU - Goddard, Sarah

AU - Gomez, Keith

AU - Gordins, Pavel

AU - Gräf, Stefan

AU - Greene, Daniel

AU - Greenhalgh, Alan

AU - Greinacher, Andreas

AU - Grigoriadou, Sofia

AU - Grozeva, Detelina

AU - Hackett, Scott

AU - Hadinnapola, Charaka

AU - Hague, Rosie

AU - Haimel, Matthias

AU - Halmagyi, Csaba

AU - Hammerton, Tracey

AU - Hart, Daniel

AU - Hayman, Grant

AU - Heemskerk, Johan W.M.

AU - Henderson, Robert

AU - Hensiek, Anke

AU - Henskens, Yvonne

AU - Herwadkar, Archana

AU - Holden, Simon

AU - Holder, Muriel

AU - Holder, Susan

AU - Hu, Fengyuan

AU - Huissoon, Aarnoud

AU - Humbert, Marc

AU - Hurst, Jane

AU - James, Roger

AU - Jolles, Stephen

AU - Josifova, Dragana

AU - Kazmi, Rashid

AU - Keeling, David

AU - Kelleher, Peter

AU - Kelly, Anne M.

AU - Kennedy, Fiona

AU - Kiely, David

AU - Kingston, Nathalie

AU - Koziell, Ania

AU - Krishnakumar, Deepa

AU - Kuijpers, Taco W.

AU - Kumararatne, Dinakantha

AU - Kurian, Manju

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AU - McJannet, Coleen

AU - Meacham, Stuart

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AU - Megy, Karyn

AU - Mehta, Sarju

AU - Michaelides, Michel

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AU - Moledina, Shahin

AU - Moore, Anthony

AU - Morrell, Nicholas

AU - Mumford, Andrew

AU - Murng, Sai

AU - Murphy, Elaine

AU - Nejentsev, Sergey

AU - Noorani, Sadia

AU - Nurden, Paquita

AU - Oksenhendler, Eric

AU - Ouwehand, Willem H.

AU - Papadia, Sofia

AU - Park, Soo Mi

AU - Parker, Alasdair

AU - Pasi, John

AU - Patch, Chris

AU - Paterson, Joan

AU - Payne, Jeanette

AU - Peacock, Andrew

AU - Peerlinck, Kathelijne

AU - Penkett, Christopher J.

AU - Pepke-Zaba, Joanna

AU - Perry, David J.

AU - Pollock, Val

AU - Polwarth, Gary

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AU - Qasim, Waseem

AU - Quinti, Isabella

AU - Rankin, Stuart

AU - Rankin, Julia

AU - Raymond, F. Lucy

AU - Rehnstrom, Karola

AU - Reid, Evan

AU - Rhodes, Christopher J.

AU - Richards, Michael

AU - Richardson, Sylvia

AU - Richter, Alex

AU - Roberts, Irene

AU - Rondina, Matthew

AU - Rosser, Elisabeth

AU - Roughley, Catherine

AU - Rue-Albrecht, Kevin

AU - Samarghitean, Crina

AU - Sanchis-Juan, Alba

AU - Sandford, Richard

AU - Santra, Saikat

AU - Sargur, Ravishankar

AU - Savic, Sinisa

AU - Schulman, Sol

AU - Schulze, Harald

AU - Scott, Richard

AU - Scully, Marie

AU - NIHR-BioResource Rare Diseases Consortium

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

VL - 100

SP - 75

EP - 90

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -