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

被引：368

作者：

Carss, Keren J. ^{[1
,2
]}

Arno, Gavin ^{[2
,3
,4
]}

Erwood, Marie ^{[1
,2
]}

Stephens, Jonathan ^{[1
,2
]}

Sanchis-Juan, Alba ^{[1
,2
]}

Hull, Sarah ^{[3
,4
]}

Megy, Karyn ^{[1
,2
]}

Grozeva, Detelina ^{[2
,5
]}

Dewhurst, Eleanor ^{[1
,2
]}

Malka, Samantha ^{[3
,4
]}

Plagnol, Vincent ^{[6
]}

Penkett, Christopher ^{[1
,2
]}

Stirrups, Kathleen ^{[1
,2
]}

Rizzo, Roberta ^{[4
]}

Wright, Genevieve ^{[4
]}

Josifova, Dragana ^{[2
,7
]}

Bitner-Glindzicz, Maria ^{[2
,8
]}

Scott, Richard H. ^{[2
,9
]}

Clement, Emma ^{[2
,10
]}

Allen, Louise ^{[2
,11
]}

Armstrong, Ruth ^{[2
,12
,13
]}

Brady, Angela F. ^{[2
,14
]}

Carmichael, Jenny ^{[2
,12
,13
]}

Chitre, Manali ^{[2
,12
,13
]}

Henderson, Robert H. H. ^{[2
,4
,10
]}

Hurst, Jane ^{[2
,10
]}

MacLaren, Robert E. ^{[2
,4
,15
]}

Murphy, Elaine ^{[2
,16
]}

Paterson, Joan ^{[2
,12
,13
]}

Rosser, Elisabeth ^{[2
,10
]}

Thompson, Dorothy A. ^{[2
,17
]}

Wakeling, Emma ^{[2
,14
]}

Ouwehand, Willem H. ^{[1
,2
]}

Michaelides, Michel ^{[2
,3
,4
]}

Moore, Anthony T. ^{[2
,3
,4
,18
]}

Webster, Andrew R. ^{[2
,3
,4
]}

Raymond, F. Lucy ^{[2
,5
]}

机构：

[1] Univ Cambridge, NHS Blood & Transplant Ctr, Dept Haematol, Cambridge CB2 0PT, England

[2] Cambridge Univ Hosp NHS Fdn Trust, NIHR BioResource Rare Dis, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[3] UCL, UCL Inst Ophthalmol, London EC1V 9EL, England

[4] Moorfields Eye Hosp, London EC1V 2PD, England

[5] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England

[6] UCL, Genet Inst, London WC1E 6BT, England

[7] Guys Hosp, Clin Genet Dept, Great Maze Pond, London SE1 9RT, England

[8] UCL Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England

[9] Great Ormond St Hosp Sick Children, North East Thames Reg Genet Serv, London WC1N 3JH, England

[10] Great Ormond St Hosp Sick Children, Great Ormond St, London WC1N 3JH, England

[11] Cambridge Univ Hosp NHS Fdn Trust, Dept Ophthalmol, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[12] Cambridge Univ Hosp NHS Fdn Trust, Dept Med Genet, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[13] Cambridge Univ Hosp NHS Fdn Trust, Dept Paediat Neurol, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[14] London North West Healthcare NHS Trust, North West Thames Reg Genet Serv, Watford Rd, Harrow HA1 3UJ, Middx, England

[15] Univ Oxford, John Radcliffe Hosp, Nuffield Lab Ophthalmol, Oxford OX3 9DU, England

[16] Natl Hosp Neurol & Neurosurg, Charles Dent Metab Unit, Queen Sq, London WC1N 3BG, England

[17] Great Ormond St Hosp Sick Children, Clin & Acad Dept Ophthalmol, London WC1N 3JH, England

[18] Univ Calif San Francisco, UCSF Sch Med, Dept Ophthalmol, San Francisco, CA 94158 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 100卷 / 01期

关键词：

EXOME; MUTATION; GENE; DYSTROPHY; DIAGNOSIS; REVEALS; PROTEIN; DISCOVERY; CAPTURE; ABCA4;

D O I：

10.1016/j.ajhg.2016.12.003

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：75 / 90

页数：16

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