Prevalence and architecture of de novo mutations in developmental disorders

被引：906

作者：

McRae, Jeremy F. ^{[1
]}

Clayton, Stephen ^{[1
]}

Fitzgerald, Tomas W. ^{[1
]}

Kaplanis, Joanna ^{[1
]}

Prigmore, Elena ^{[1
]}

Rajan, Diana ^{[1
]}

Sifrim, Alejandro ^{[1
]}

Aitken, Stuart ^{[2
]}

Akawi, Nadia ^{[1
]}

Alvi, Mohsan ^{[3
]}

Ambridge, Kirsty ^{[1
]}

Barrett, Daniel M. ^{[1
]}

Bayzetinova, Tanya ^{[1
]}

Jones, Philip ^{[1
]}

Jones, Wendy D. ^{[1
]}

King, Daniel ^{[1
]}

Krishnappa, Netravathi ^{[1
]}

Mason, Laura E. ^{[1
]}

Singh, Tarjinder ^{[1
]}

Tivey, Adrian R. ^{[1
]}

Ahmed, Munaza ^{[4
,5
,6
]}

Anjum, Uruj ^{[7
]}

Archer, Hayley ^{[8
,9
]}

Armstrong, Ruth ^{[10
]}

Awada, Jana ^{[1
]}

Balasubramanian, Meena ^{[11
]}

Banka, Siddharth ^{[12
]}

Baralle, Diana ^{[4
,5
]}

Barnicoat, Angela ^{[13
]}

Batstone, Paul ^{[14
]}

Baty, David ^{[15
]}

Bennett, Chris ^{[16
]}

Berg, Jonathan ^{[15
]}

Bernhard, Birgitta ^{[17
]}

Bevan, A. Paul ^{[1
]}

Bitner-Glindzicz, Maria ^{[13
]}

Blair, Edward ^{[18
]}

Blyth, Moira ^{[16
]}

Bohanna, David ^{[19
]}

Bourdon, Louise ^{[17
]}

Bourn, David ^{[20
]}

Bradley, Lisa ^{[21
]}

Brady, Angela ^{[17
]}

Brent, Simon ^{[1
]}

Brewer, Carole ^{[22
]}

Brunstrom, Kate ^{[13
]}

Bunyan, David J. ^{[4
,5
,6
]}

Burn, John ^{[20
]}

Canham, Natalie ^{[17
]}

Castle, Bruce ^{[22
]}

机构：

[1] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England

[2] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, MRC IGMM, Edinburgh EH4 2XU, Midlothian, Scotland

[3] Univ Oxford, Dept Engn Sci, Parks Rd, Oxford OX1 3PJ, England

[4] Southampton Univ Hosp, Princess Anne Hosp, Wessex Clin Genet Serv, Coxford Rd, Southampton SO16 5YA, Hants, England

[5] Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Odstock Rd, Salisbury SP2 8BJ, Wilts, England

[6] Univ Southampton, Fac Med, Bldg 85,Life Sci Bldg,Highfield Campus, Southampton SO17, Hants, England

[7] Univ London, South West Thames Reg Genet Ctr, St Georges Healthcare NHS Trust, Cranmer Terrace, London SW17 0RE, England

[8] Univ Wales Hosp, Inst Med Genet, Heath Pk, Cardiff CF14 4XW, Wales

[9] Glan Clwyd Gen Hosp, Dept Clin Genet, Block 12, Rhyl, Denbigh, Wales

[10] East Anglian Med Genet Serv, Cambridge Univ Hosp, NHS Fdn Trust, Box 134,Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[11] Sheffield Reg Genet Serv, Sheffield Childrens NHS Trust, Western Bank, Sheffield S10 2TH, S Yorkshire, England

[12] Manchester Acad Hlth Sci Ctr, St Marys Hosp, Manchester Ctr Genom Med, Cent Manchester Univ Hosp NHS Fdn Trust, Manchester M13 9WL, Lancs, England

[13] Hosp Children NHS Fdn Trust, Great Ormond St Hosp, North East Thames Reg Genet Serv, Great Ormond St, London WC1N 3JH, England

[14] Dept Med Genet Med Sch, North Scotland Reg Genet Serv, NHS Grampian, Foresterhill, Aberdeen AB25 2ZD, Scotland

[15] Ninewells Hosp, East Scotland Reg Genet Serv, Dept Pathol, Human Genet Unit NHS Tayside, Dundee DD1 9SY, Scotland

[16] Leeds Teaching Hosp NHS Trust, Chapel Allerton Hosp, Dept Clin Genet, Yorkshire Reg Genet Serv, Chapeltown Rd, Leeds LS7 4SA, W Yorkshire, England

[17] North West London Hosp NHS Trust, North West Thames Reg Genet Ctr, Kennedy Galton Ctr, Northwick Pk & St Marks NHS Trust Watford Rd, Harrow HA1 3UJ, Middx, England

[18] Oxford Radcliffe Hosp NHS Trust, Oxford Reg Genet Serv, Churchill Old Rd, Oxford OX3 7LJ, England

[19] Birmingham Womens Hosp, Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England

[20] Newcastle Tyne Hosp NHS Fdn Trust, Inst Human Genet, Int Ctr Life, Northern Genet Serv, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[21] Belfast City Hosp, Northern Ireland Reg Genet Ctr, Belfast Hlth & Social Care Trust, Lisburn Rd, Belfast, Antrim, North Ireland

[22] Royal Devon & Exeter Hosp Heavitree, Royal Devon & Exeter NHS Fdn Trust, Peninsula Clin Genet Serv, Dept Clin Genet, Gladstone Rd, Exeter EX1 2ED, Devon, England

[23] Guys Hosp, Guys & St Thomas NHS Fdn Trust, South East Thames Reg Genet Ctr, Great Maze Pond, London SE1 9RT, England

[24] Univ Hosp Leicester NHS Trust, Leicester Genet Ctr, Leicester Royal Infirm NHS Trust, Leicester LE1 5WW, Leics, England

[25] Nottingham Univ Hosp NHS Trust, City Hosp Campus, Nottingham Reg Genet Serv, Hucknall Rd, Nottingham NG5, England

[26] West Scotland Reg Genet Serv, Inst Med Genet, Yorkhill Hosp, NHS Greater Glasgow & Clyde, Glasgow G3 8SJ, Lanark, Scotland

[27] St Michaels Hosp, Univ Hosp Bristol NHS Fdn Trust, Bristol Genet Serv Avon, St Michaels Hill, Somerset, NJ USA

[28] Royal Liverpool Childrens Hosp Alder Hey, Dept Clin Genet, Liverpool Womens NHS Fdn Trust, Merseyside & Cheshire Genet Serv, Eaton Rd, Liverpool L12 2AP, Merseyside, England

[29] Our Ladys Childrens Hosp, Natl Ctr Med Genet, Dublin 12, Ireland

[30] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet Gynaecol, Womens Ctr, Oxford OX3 9DU, England

[31] Univ Oxford, Dept Engn Sci, Inst Biomed Engn, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England

[32] Univ Oxford, Big Data Inst, Roosevelt Dr, Oxford OX3 7LF, England

[33] Univ Oxford, Nuffield Dept Populat Hlth, Ethox Ctr, Old Rd Campus, Oxford OX3 7LF, England

来源：

NATURE | 2017年 / 542卷 / 7642期

基金：

英国惠康基金;

关键词：

INTELLECTUAL DISABILITY; HEART-DEFECTS; DISCOVERY; GENETICS; GENOME; GENES; METAANALYSIS; FRAMEWORK; VARIANTS; SEQUENCE;

D O I：

10.1038/nature21062

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.

引用

页码：433 / +

页数：20

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