Hurles, Matthew

Hurles Group

Matthew Hurles leads a research group focused on deciphering the genetic causes of severe developmental disorders, and understanding how DNA mutates as it is passed from generation to generation.

I am fascinated by human genetic variation, its clinical impact, its underlying mutational origins and its potential to illuminate human prehistory.

I am dedicated to applying new genetic technologies to improve the diagnosis of patients with rare genetic conditions. I believe understanding the genetic causes of these disorders, and their underlying biological mechanisms, will give us fundamental insights into human development.

I lead the Deciphering Developmental Disorders (DDD) Study, a collaboration between 14,000 families with children with severe, undiagnosed developmental disorders, all 24 clinical genetic centres in the UK and Ireland, and the Wellcome Trust Sanger Institute. Together we are understanding the diverse genetic landscape of these disorders, and applying this knowledge to achieve improved diagnostic testing.

I also lead the Prenatal Assessment of Genomes and Exomes (PAGE) Study, a collaboration between pregnant mothers and their partners, a network of UK Fetal Medicine Centres caring for these pregnant women and the Wellcome Trust Sanger Institute. Together we are investigating the genetic causes of developmental anomalies that are identified during prenatal ultrasound screening, with the aim of improving the prognostic information that can be provided to parents.

The work of my research group has been characterized by rapid adoption of new technologies for assaying genetic variation, development of novel analytical strategies for making sense from large datasets and thoughtful application of these tools for advancing our understanding of human genetic diseases. More recently, our highly collaborative research has had increasing translational impact, resulting in genetic diagnoses for over a thousand children with previously undiagnosed developmental disorders, and leading to the founding of a start-up company (Congenica Ltd) to provide sustainable genetic diagnostic services to the NHS and other healthcare providers.

I believe we have a moral imperative to give patients and their families the opportunity to share their genetic data anonymously, to enable them to benefit from having the greatest possible number of researchers and clinicians analysing their data. Together with Helen Firth, I lead the DECIPHER initiative that is enabling rare disease patients to share anonymised genetic and clinical data globally.

My group is applying the latest technologies to edit the DNA of cells and model organisms to develop experimental models of newly identified genetic disorders that enable us to characterise the biology of the disorder, and to identiy opportunities for developing therapies.

Publications

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M et al.

Nature genetics 2015;47;11;1363-9

PUBMED: 26437029; DOI: 10.1038/ng.3410
Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study

Nature 2015;519;7542;223-8

PUBMED: 25533962; DOI: 10.1038/nature14135
Rare variants in NR2F2 cause congenital heart defects in humans.

Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP et al.

American journal of human genetics 2014;94;4;574-85

PUBMED: 24702954; PMC: 3980509; DOI: 10.1016/j.ajhg.2014.03.007
Variation in genome-wide mutation rates within and between human families.

Conrad DF, Keebler JE, DePristo MA, Lindsay SJ, Zhang Y et al.

Nature genetics 2011;43;7;712-4

PUBMED: 21666693; PMC: 3322360; DOI: 10.1038/ng.862
A map of human genome variation from population-scale sequencing.

1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD et al.

Nature 2010;467;7319;1061-73

PUBMED: 20981092; PMC: 3042601; DOI: 10.1038/nature09534
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD et al.

Nature 2010;464;7289;713-20

PUBMED: 20360734; PMC: 2892339; DOI: 10.1038/nature08979
Origins and functional impact of copy number variation in the human genome.

Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O et al.

Nature 2010;464;7289;704-12

PUBMED: 19812545; PMC: 3330748; DOI: 10.1038/nature08516
Large, rare chromosomal deletions associated with severe early-onset obesity.

Bochukova EG, Huang N, Keogh J, Henning E, Purmann C et al.

Nature 2010;463;7281;666-70

PUBMED: 19966786; PMC: 3108883; DOI: 10.1038/nature08689
Germline rates of de novo meiotic deletions and duplications causing several genomic disorders.

Turner DJ, Miretti M, Rajan D, Fiegler H, Carter NP et al.

Nature genetics 2008;40;1;90-5

PUBMED: 18059269; PMC: 2669897; DOI: 10.1038/ng.2007.40
Global variation in copy number in the human genome.

Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH et al.

Nature 2006;444;7118;444-54

PUBMED: 17122850; PMC: 2669898; DOI: 10.1038/nature05329

"Matching" consent to purpose: The example of the Matchmaker Exchange.

Dyke SOM, Knoppers BM, Hamosh A, Firth HV, Hurles M et al.

Human mutation 2017

PUBMED: 28699299; DOI: 10.1002/humu.23278
An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Liu P, Yuan B, Carvalho CM, Wuster A, Walter K et al.

Cell 2017;168;5;830-842.e7

PUBMED: 28235197; DOI: 10.1016/j.cell.2017.01.037
Prevalence and architecture of de novo mutations in developmental disorders.

Deciphering Developmental Disorders Study

Nature 2017;542;7642;433-438

PUBMED: 28135719; DOI: 10.1038/nature21062

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.

Muona M, Ishimura R, Laari A, Ichimura Y, Linnankivi T et al.

American journal of human genetics 2016;99;3;683-94

PUBMED: 27545674; PMC: 5010641; DOI: 10.1016/j.ajhg.2016.06.020
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH et al.

Nature genetics 2016;48;9;1060-5

PUBMED: 27479907; DOI: 10.1038/ng.3627
Prenatal Whole Exome Sequencing; the Views of Clinicians, Scientists, Genetic Counsellors and Patient Representatives.

Quinlan-Jones E, Kilby MD, Greenfield S, Parker M, McMullan D et al.

Prenatal diagnosis 2016

PUBMED: 27550507; DOI: 10.1002/pd.4916
De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

Priest JR, Osoegawa K, Mohammed N, Nanda V, Kundu R et al.

PLoS genetics 2016;12;4;e1005963

PUBMED: 27058611; PMC: 4825975; DOI: 10.1371/journal.pgen.1005963
Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L et al.

Nature neuroscience 2016;19;4;571-7

PUBMED: 26974950; DOI: 10.1038/nn.4267
Clinical delineation of the PACS1-related syndrome--Report on 19 patients.

Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH et al.

American journal of medical genetics. Part A 2016;170;3;670-5

PUBMED: 26842493; DOI: 10.1002/ajmg.a.37476
Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.

D'Alessandro LC, Al Turki S, Manickaraj AK, Manase D, Mulder BJ et al.

Genetics in medicine : official journal of the American College of Medical Genetics 2016;18;2;189-98

PUBMED: 25996639; DOI: 10.1038/gim.2015.60
Timing, rates and spectra of human germline mutation.

Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB et al.

Nature genetics 2016;48;2;126-133

PUBMED: 26656846; PMC: 4731925; DOI: 10.1038/ng.3469
Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research.

Middleton A, Morley KI, Bragin E, Firth HV, Hurles ME et al.

European journal of human genetics : EJHG 2016;24;1;21-9

PUBMED: 25920556; PMC: 4795240; DOI: 10.1038/ejhg.2015.58
Consent Codes: Upholding Standard Data Use Conditions.

Dyke SO, Philippakis AA, Rambla De Argila J, Paltoo DN, Luetkemeier ES et al.

PLoS genetics 2016;12;1;e1005772

PUBMED: 26796797; PMC: 4721915; DOI: 10.1371/journal.pgen.1005772

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J et al.

Human mutation 2015;36;12;1197-204

PUBMED: 26350204; PMC: 4833192; DOI: 10.1002/humu.22901
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M et al.

Nature genetics 2015;47;11;1363-9

PUBMED: 26437029; DOI: 10.1038/ng.3410
A global reference for human genetic variation.

1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP et al.

Nature 2015;526;7571;68-74

PUBMED: 26432245; PMC: 4750478; DOI: 10.1038/nature15393
The Matchmaker Exchange: a platform for rare disease gene discovery.

Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA et al.

Human mutation 2015;36;10;915-21

PUBMED: 26295439; PMC: 4610002; DOI: 10.1002/humu.22858
The UK10K project identifies rare variants in health and disease.

UK10K Consortium, Walter K, Min JL, Huang J, Crooks L et al.

Nature 2015;526;7571;82-90

PUBMED: 26367797; PMC: 4773891; DOI: 10.1038/nature14962
Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER.

Chatzimichali EA, Brent S, Hutton B, Perrett D, Wright CF et al.

Human mutation 2015;36;10;941-9

PUBMED: 26220709; PMC: 4832335; DOI: 10.1002/humu.22842
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ et al.

The Journal of clinical investigation 2015;125;8;3051-62

PUBMED: 26168268; PMC: 4623570; DOI: 10.1172/JCI79860
Potential research participants support the return of raw sequence data.

Middleton A, Wright CF, Morley KI, Bragin E, Firth HV et al.

Journal of medical genetics 2015;52;8;571-4

PUBMED: 25995218; PMC: 4518751; DOI: 10.1136/jmedgenet-2015-103119
Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.

Jinks RN, Puffenberger EG, Baple E, Harding B, Crino P et al.

Brain : a journal of neurology 2015;138;Pt 8;2173-90

PUBMED: 26070982; PMC: 4511861; DOI: 10.1093/brain/awv153
Copy number variation in the human Y chromosome in the UK population.

Wei W, Fitzgerald TW, Fitzgerald T, Ayub Q, Massaia A et al.

Human genetics 2015;134;7;789-800

PUBMED: 25957587; PMC: 4460274; DOI: 10.1007/s00439-015-1562-5
Mosaic structural variation in children with developmental disorders.

King DA, Jones WD, Crow YJ, Dominiczak AF, Foster NA et al.

Human molecular genetics 2015;24;10;2733-45

PUBMED: 25634561; PMC: 4406290; DOI: 10.1093/hmg/ddv033
Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A et al.

Neurology 2015;84;17;1745-50

PUBMED: 25832664; PMC: 4424132; DOI: 10.1212/WNL.0000000000001523
Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF et al.

Lancet (London, England) 2015;385;9975;1305-14

PUBMED: 25529582; PMC: 4392068; DOI: 10.1016/S0140-6736(14)61705-0
No expectation to share incidental findings in genomic research.

Middleton A, Morley KI, Bragin E, Firth HV, Hurles ME et al.

Lancet (London, England) 2015;385;9975;1289-90

PUBMED: 25529584; DOI: 10.1016/S0140-6736(14)62119-X
Absence of heterozygosity due to template switching during replicative rearrangements.

Carvalho CM, Pfundt R, King DA, Lindsay SJ, Zuccherato LW et al.

American journal of human genetics 2015;96;4;555-64

PUBMED: 25799105; PMC: 4385179; DOI: 10.1016/j.ajhg.2015.01.021
Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling.

Baker K, Gordon SL, Grozeva D, van Kogelenberg M, Roberts NY et al.

The Journal of clinical investigation 2015;125;4;1670-8

PUBMED: 25705886; PMC: 4396464; DOI: 10.1172/JCI79765
The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline.

Adewoye AB, Lindsay SJ, Dubrova YE and Hurles ME

Nature communications 2015;6;6684

PUBMED: 25809527; PMC: 4389250; DOI: 10.1038/ncomms7684
Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes.

Cooper NJ, Shtir CJ, Smyth DJ, Guo H, Swafford AD et al.

Human molecular genetics 2015;24;6;1774-90

PUBMED: 25424174; PMC: 4381751; DOI: 10.1093/hmg/ddu581
Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms.

Abyzov A, Li S, Kim DR, Mohiyuddin M, Stütz AM et al.

Nature communications 2015;6;7256

PUBMED: 26028266; PMC: 4451611; DOI: 10.1038/ncomms8256
Prenatal exome sequencing for fetuses with structural abnormalities: the next step.

Hillman SC, Willams D, Carss KJ, McMullan DJ, Hurles ME and Kilby MD

Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2015;45;1;4-9

PUBMED: 25157891; DOI: 10.1002/uog.14653
Using population data for assessing next-generation sequencing performance.

Houniet DT, Rahman TJ, Al Turki S, Hurles ME, Xu Y et al.

Bioinformatics (Oxford, England) 2015;31;1;56-61

PUBMED: 25236458; PMC: 4271148; DOI: 10.1093/bioinformatics/btu606

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy.

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS et al.

Nature genetics 2014;46;12;1283-92

PUBMED: 25344692; PMC: 4676084; DOI: 10.1038/ng.3122
Exome Sequencing in Fetuses with Structural Malformations.

Mackie FL, Carss KJ, Hillman SC, Hurles ME and Kilby MD

Journal of clinical medicine 2014;3;3;747-62

PUBMED: 26237476; PMC: 4449643; DOI: 10.3390/jcm3030747
Cis and trans effects of human genomic variants on gene expression.

Bryois J, Buil A, Evans DM, Kemp JP, Montgomery SB et al.

PLoS genetics 2014;10;7;e1004461

PUBMED: 25010687; PMC: 4091791; DOI: 10.1371/journal.pgen.1004461
Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.

Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER et al.

Human molecular genetics 2014;23;12;3269-77

PUBMED: 24476948; PMC: 4030780; DOI: 10.1093/hmg/ddu038
Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.

Rainger J, Pehlivan D, Johansson S, Bengani H, Sanchez-Pulido L et al.

American journal of human genetics 2014;94;6;915-23

PUBMED: 24906020; PMC: 4121478; DOI: 10.1016/j.ajhg.2014.05.005
De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.

Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H et al.

American journal of human genetics 2014;94;4;618-24

PUBMED: 24680889; PMC: 3980521; DOI: 10.1016/j.ajhg.2014.03.006
Rare variants in NR2F2 cause congenital heart defects in humans.

Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP et al.

American journal of human genetics 2014;94;4;574-85

PUBMED: 24702954; PMC: 3980509; DOI: 10.1016/j.ajhg.2014.03.007
A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders.

King DA, Fitzgerald TW, Miller R, Canham N, Clayton-Smith J et al.

Genome research 2014;24;4;673-87

PUBMED: 24356988; PMC: 3975066; DOI: 10.1101/gr.160465.113
The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age.

MacArthur JA, Spector TD, Lindsay SJ, Mangino M, Gill R et al.

PLoS genetics 2014;10;3;e1004195

PUBMED: 24603440; PMC: 3945173; DOI: 10.1371/journal.pgen.1004195
Characterizing genetic variants for clinical action.

Ramos EM, Din-Lovinescu C, Berg JS, Brooks LD, Duncanson A et al.

American journal of medical genetics. Part C, Seminars in medical genetics 2014;166C;1;93-104

PUBMED: 24634402; PMC: 4158437; DOI: 10.1002/ajmg.c.31386
Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

Mulle JG, Pulver AE, McGrath JA, Wolyniec PS, Dodd AF et al.

Biological psychiatry 2014;75;5;371-7

PUBMED: 23871472; PMC: 3838485; DOI: 10.1016/j.biopsych.2013.05.040
Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects.

Williamson KA, Rainger J, Floyd JA, Ansari M, Meynert A et al.

American journal of human genetics 2014;94;2;295-302

PUBMED: 24462371; PMC: 3928658; DOI: 10.1016/j.ajhg.2014.01.001
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.

Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S et al.

Nature genetics 2014;46;2;188-93

PUBMED: 24336167; DOI: 10.1038/ng.2851
Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures.

Baple EL, Maroofian R, Chioza BA, Izadi M, Cross HE et al.

American journal of human genetics 2014;94;1;87-94

PUBMED: 24239382; PMC: 3882725; DOI: 10.1016/j.ajhg.2013.10.001
A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes.

Zanda M, Onengut-Gumuscu S, Walker N, Shtir C, Gallo D et al.

PLoS genetics 2014;10;5;e1004367

PUBMED: 24875393; PMC: 4038470; DOI: 10.1371/journal.pgen.1004367
DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation.

Bragin E, Chatzimichali EA, Wright CF, Hurles ME, Firth HV et al.

Nucleic acids research 2014;42;Database issue;D993-D1000

PUBMED: 24150940; PMC: 3965078; DOI: 10.1093/nar/gkt937
Deletions of chromosomal regulatory boundaries are associated with congenital disease.

Ibn-Salem J, Köhler S, Love MI, Chung HR, Huang N et al.

Genome biology 2014;15;9;423

PUBMED: 25315429; PMC: 4180961; DOI: 10.1186/s13059-014-0423-1
Extreme growth failure is a common presentation of ligase IV deficiency.

Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M et al.

Human mutation 2014;35;1;76-85

PUBMED: 24123394; PMC: 3995017; DOI: 10.1002/humu.22461
High throughput exome coverage of clinically relevant cardiac genes.

Manase D, D'Alessandro LC, Manickaraj AK, Al Turki S, Hurles ME and Mital S

BMC medical genomics 2014;7;67

PUBMED: 25496018; PMC: 4272796; DOI: 10.1186/s12920-014-0067-8

COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.

Pitceathly RD, Taanman JW, Rahman S, Meunier B, Sadowski M et al.

JAMA neurology 2013;70;12;1556-61

PUBMED: 24100867; DOI: 10.1001/jamaneurol.2013.3242
Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.

Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R et al.

Brain : a journal of neurology 2013;136;Pt 12;3618-24

PUBMED: 24103911; PMC: 3859217; DOI: 10.1093/brain/awt270
Reduced burden of very large and rare CNVs in bipolar affective disorder.

Grozeva D, Kirov G, Conrad DF, Barnes CP, Hurles M et al.

Bipolar disorders 2013;15;8;893-8

PUBMED: 24127788; DOI: 10.1111/bdi.12125
Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy.

Schmidts M, Vodopiutz J, Christou-Savina S, Cortés CR, McInerney-Leo AM et al.

American journal of human genetics 2013;93;5;932-44

PUBMED: 24183451; PMC: 3824113; DOI: 10.1016/j.ajhg.2013.10.003
DeNovoGear: de novo indel and point mutation discovery and phasing.

Ramu A, Noordam MJ, Schwartz RS, Wuster A, Hurles ME et al.

Nature methods 2013;10;10;985-7

PUBMED: 23975140; PMC: 4003501; DOI: 10.1038/nmeth.2611
Cerebral organoids model human brain development and microcephaly.

Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS et al.

Nature 2013;501;7467;373-9

PUBMED: 23995685; PMC: 3817409; DOI: 10.1038/nature12517
TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.

Wiszniewski W, Hunter JV, Hanchard NA, Willer JR, Shaw C et al.

American journal of human genetics 2013;93;2;197-210

PUBMED: 23810381; PMC: 3738832; DOI: 10.1016/j.ajhg.2013.05.027
Empirical research on the ethics of genomic research.

Middleton A, Parker M, Wright CF, Bragin E, Hurles ME and DDD Study

American journal of medical genetics. Part A 2013;161A;8;2099-101

PUBMED: 23813698; PMC: 3884757; DOI: 10.1002/ajmg.a.36067
Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M et al.

American journal of human genetics 2013;93;1;29-41

PUBMED: 23768512; PMC: 3710768; DOI: 10.1016/j.ajhg.2013.05.009
NDUFA4 Mutations Underlie Dysfunction of a Cytochrome c Oxidase Subunit Linked to Human Neurological Disease.

Pitceathly RD, Rahman S, Wedatilake Y, Polke JM, Cirak S et al.

Cell reports 2013

PUBMED: 23746447; DOI: 10.1016/j.celrep.2013.05.005
Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice.

Mohun T, Adams DJ, Baldock R, Bhattacharya S, Copp AJ et al.

Disease models & mechanisms 2013;6;3;562-6

PUBMED: 23519034; PMC: 3634640; DOI: 10.1242/dmm.011957
Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.

Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S et al.

Nature genetics 2013;45;5;513-7

PUBMED: 23563609; PMC: 4106235; DOI: 10.1038/ng.2607
Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.

Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA et al.

Human mutation 2013;34;5;714-24

PUBMED: 23418020; PMC: 4226634; DOI: 10.1002/humu.22294
Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan.

Stevens E, Carss KJ, Cirak S, Foley AR, Torelli S et al.

American journal of human genetics 2013;92;3;354-65

PUBMED: 23453667; PMC: 3591840; DOI: 10.1016/j.ajhg.2013.01.016
Quantifying single nucleotide variant detection sensitivity in exome sequencing.

Meynert AM, Bicknell LS, Hurles ME, Jackson AP and Taylor MS

BMC bioinformatics 2013;14;195

PUBMED: 23773188; PMC: 3695811; DOI: 10.1186/1471-2105-14-195

Bayesian refinement of association signals for 14 loci in 3 common diseases.

Wellcome Trust Case Control Consortium, Maller JB, McVean G, Byrnes J, Vukcevic D et al.

Nature genetics 2012;44;12;1294-301

PUBMED: 23104008; PMC: 3791416; DOI: 10.1038/ng.2435
An integrated map of genetic variation from 1,092 human genomes.

1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA et al.

Nature 2012;491;7422;56-65

PUBMED: 23128226; PMC: 3498066; DOI: 10.1038/nature11632
DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders.

Swaminathan GJ, Bragin E, Chatzimichali EA, Corpas M, Bevan AP et al.

Human molecular genetics 2012;21;R1;R37-44

PUBMED: 22962312; PMC: 3459644; DOI: 10.1093/hmg/dds362
Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry.

Olbrich H, Schmidts M, Werner C, Onoufriadis A, Loges NT et al.

American journal of human genetics 2012;91;4;672-84

PUBMED: 23022101; PMC: 3484652; DOI: 10.1016/j.ajhg.2012.08.016

A map of human genome variation from population-scale sequencing.

1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD et al.

Nature 2010;467;7319;1061-73

PUBMED: 20981092; PMC: 3042601; DOI: 10.1038/nature09534
Characterising and predicting haploinsufficiency in the human genome.

Huang N, Lee I, Marcotte EM and Hurles ME

PLoS genetics 2010;6;10;e1001154

PUBMED: 20976243; PMC: 2954820; DOI: 10.1371/journal.pgen.1001154
Integrating common and rare genetic variation in diverse human populations.

International HapMap 3 Consortium, Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM et al.

Nature 2010;467;7311;52-8

PUBMED: 20811451; PMC: 3173859; DOI: 10.1038/nature09298
Mutation spectrum revealed by breakpoint sequencing of human germline CNVs.

Conrad DF, Bird C, Blackburne B, Lindsay S, Mamanova L et al.

Nature genetics 2010;42;5;385-91

PUBMED: 20364136; PMC: 3428939; DOI: 10.1038/ng.564
Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing.

Park H, Kim JI, Ju YS, Gokcumen O, Mills RE et al.

Nature genetics 2010;42;5;400-5

PUBMED: 20364138; PMC: 3329635; DOI: 10.1038/ng.555
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD et al.

Nature 2010;464;7289;713-20

PUBMED: 20360734; PMC: 2892339; DOI: 10.1038/nature08979
Origins and functional impact of copy number variation in the human genome.

Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O et al.

Nature 2010;464;7289;704-12

PUBMED: 19812545; PMC: 3330748; DOI: 10.1038/nature08516
Large, rare chromosomal deletions associated with severe early-onset obesity.

Bochukova EG, Huang N, Keogh J, Henning E, Purmann C et al.

Nature 2010;463;7281;666-70

PUBMED: 19966786; PMC: 3108883; DOI: 10.1038/nature08689

Accurate whole human genome sequencing using reversible terminator chemistry.

Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J et al.

Nature 2008;456;7218;53-9

PUBMED: 18987734; PMC: 2581791; DOI: 10.1038/nature07517
Copy number variation and evolution in humans and chimpanzees.

Perry GH, Yang F, Marques-Bonet T, Murphy C, Fitzgerald T et al.

Genome research 2008;18;11;1698-710

PUBMED: 18775914; PMC: 2577862; DOI: 10.1101/gr.082016.108
A robust statistical method for case-control association testing with copy number variation.

Barnes C, Plagnol V, Fitzgerald T, Redon R, Marchini J et al.

Nature genetics 2008;40;10;1245-52

PUBMED: 18776912; PMC: 2784596; DOI: 10.1038/ng.206
Adaptive evolution of UGT2B17 copy-number variation.

Xue Y, Sun D, Daly A, Yang F, Zhou X et al.

American journal of human genetics 2008;83;3;337-46

PUBMED: 18760392; PMC: 2556428; DOI: 10.1016/j.ajhg.2008.08.004
Long-range, high-throughput haplotype determination via haplotype-fusion PCR and ligation haplotyping.

Turner DJ, Tyler-Smith C and Hurles ME

Nucleic acids research 2008;36;13;e82

PUBMED: 18562465; PMC: 2490767; DOI: 10.1093/nar/gkn373
Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.

Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H et al.

Nature genetics 2008;40;6;722-9

PUBMED: 18438408; PMC: 2705838; DOI: 10.1038/ng.128
The functional impact of structural variation in humans.

Hurles ME, Dermitzakis ET and Tyler-Smith C

Trends in genetics : TIG 2008;24;5;238-45

PUBMED: 18378036; PMC: 2869026; DOI: 10.1016/j.tig.2008.03.001
Germline rates of de novo meiotic deletions and duplications causing several genomic disorders.

Turner DJ, Miretti M, Rajan D, Fiegler H, Carter NP et al.

Nature genetics 2008;40;1;90-5

PUBMED: 18059269; PMC: 2669897; DOI: 10.1038/ng.2007.40

Paired-end mapping reveals extensive structural variation in the human genome.

Korbel JO, Urban AE, Affourtit JP, Godwin B, Grubert F et al.

Science (New York, N.Y.) 2007;318;5849;420-6

PUBMED: 17901297; PMC: 2674581; DOI: 10.1126/science.1149504
The population genetics of structural variation.

Conrad DF and Hurles ME

Nature genetics 2007;39;7 Suppl;S30-6

PUBMED: 17597779; PMC: 2716079; DOI: 10.1038/ng2042
Challenges and standards in integrating surveys of structural variation.

Scherer SW, Lee C, Birney E, Altshuler DM, Eichler EE et al.

Nature genetics 2007;39;7 Suppl;S7-15

PUBMED: 17597783; PMC: 2698291; DOI: 10.1038/ng2093
Relative impact of nucleotide and copy number variation on gene expression phenotypes.

Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C et al.

Science (New York, N.Y.) 2007;315;5813;848-53

PUBMED: 17289997; PMC: 2665772; DOI: 10.1126/science.1136678
Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization.

Marioni JC, Thorne NP, Valsesia A, Fitzgerald T, Redon R et al.

Genome biology 2007;8;10;R228

PUBMED: 17961237; PMC: 2246302; DOI: 10.1186/gb-2007-8-10-r228

Accurate and reliable high-throughput detection of copy number variation in the human genome.

Fiegler H, Redon R, Andrews D, Scott C, Andrews R et al.

Genome research 2006;16;12;1566-74

PUBMED: 17122085; PMC: 1665640; DOI: 10.1101/gr.5630906
Genome assembly comparison identifies structural variants in the human genome.

Khaja R, Zhang J, MacDonald JR, He Y, Joseph-George AM et al.

Nature genetics 2006;38;12;1413-8

PUBMED: 17115057; PMC: 2674632; DOI: 10.1038/ng1921
Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays.

Komura D, Shen F, Ishikawa S, Fitch KR, Chen W et al.

Genome research 2006;16;12;1575-84

PUBMED: 17122084; PMC: 1665641; DOI: 10.1101/gr.5629106
Global variation in copy number in the human genome.

Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH et al.

Nature 2006;444;7118;444-54

PUBMED: 17122850; PMC: 2669898; DOI: 10.1038/nature05329
A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination.

Lindsay SJ, Khajavi M, Lupski JR and Hurles ME

American journal of human genetics 2006;79;5;890-902

PUBMED: 17033965; PMC: 1698570; DOI: 10.1086/508709
Assaying chromosomal inversions by single-molecule haplotyping.

Turner DJ, Shendure J, Porreca G, Church G, Green P et al.

Nature methods 2006;3;6;439-45

PUBMED: 16721377; PMC: 2690135; DOI: 10.1038/nmeth881
Male demography in East Asia: a north-south contrast in human population expansion times.

Xue Y, Zerjal T, Bao W, Zhu S, Shu Q et al.

Genetics 2006;172;4;2431-9

PUBMED: 16489223; PMC: 1456369; DOI: 10.1534/genetics.105.054270
A high-resolution survey of deletion polymorphism in the human genome.

Conrad DF, Andrews TD, Carter NP, Hurles ME and Pritchard JK

Nature genetics 2006;38;1;75-81

PUBMED: 16327808; DOI: 10.1038/ng1697
Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.

Traherne JA, Horton R, Roberts AN, Miretti MM, Hurles ME et al.

PLoS genetics 2006;2;1;e9

PUBMED: 16440057; PMC: 1331980; DOI: 10.1371/journal.pgen.0020009
Recombination hotspots in nonallelic homologous recombination

HURLES,M.E. and Lupski,J.R.;

Genomic Disorders: The Genomic Basis of Disease 2006;Chapter 24;341-355

DOI: 10.1007/978-1-59745-039-3_24; URL: http://link.springer.com/chapter.../10.1007/978-1-59745-039-3_24#page-1
Y-chromosomal rearrangements and azoospermia

Hurles,M.E. and Tyler-Smith,C.

Genomic Disorders: The Genomic Basis of Disease 2006;19;273-288

DOI: 10.1007/978-1-59745-039-3_19; URL: http://link.springer.com/chapter.../10.1007/978-1-59745-039-3_19#page-1

Shotgun haplotyping: a novel method for surveying allelic sequence variation.

Lindsay SJ, Bonfield JK and Hurles ME

Nucleic acids research 2005;33;18;e152

PUBMED: 16221968; PMC: 1253838; DOI: 10.1093/nar/gni152
How homologous recombination generates a mutable genome.

Hurles M

Human genomics 2005;2;3;179-86

PUBMED: 16197735; PMC: 3525126
The dual origin of the Malagasy in Island Southeast Asia and East Africa: evidence from maternal and paternal lineages.

Hurles ME, Sykes BC, Jobling MA and Forster P

American journal of human genetics 2005;76;5;894-901

PUBMED: 15793703; PMC: 1199379; DOI: 10.1086/430051
Don't mix radiocarbon and calendar years.

Tyler-Smith C, Hurles ME and Jobling MA

Nature 2005;434;7034;697

PUBMED: 15815601; DOI: 10.1038/434697c
The DNA sequence of the human X chromosome.

Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K et al.

Nature 2005;434;7031;325-37

PUBMED: 15772651; PMC: 2665286; DOI: 10.1038/nature03440

Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots.

Hurles ME, Willey D, Matthews L and Hussain SS

Genome biology 2004;5;8;R55

PUBMED: 15287977; PMC: 507880; DOI: 10.1186/gb-2004-5-8-r55

Career/Research Highlights

Three new genetic conditions identified in the DDD study, with children from different parts of the UK sharing identical mutations in their DNA

Dr Matthew Hurles | Head of Human Genetics and Senior Group Leader

Publications

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Large-scale discovery of novel genetic causes of developmental disorders.

Rare variants in NR2F2 cause congenital heart defects in humans.

Variation in genome-wide mutation rates within and between human families.

A map of human genome variation from population-scale sequencing.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Origins and functional impact of copy number variation in the human genome.

Large, rare chromosomal deletions associated with severe early-onset obesity.

Germline rates of de novo meiotic deletions and duplications causing several genomic disorders.

Global variation in copy number in the human genome.

"Matching" consent to purpose: The example of the Matchmaker Exchange.

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Prevalence and architecture of de novo mutations in developmental disorders.

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Prenatal Whole Exome Sequencing; the Views of Clinicians, Scientists, Genetic Counsellors and Patient Representatives.

De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders.

Clinical delineation of the PACS1-related syndrome--Report on 19 patients.

Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.

Timing, rates and spectra of human germline mutation.

Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research.

Consent Codes: Upholding Standard Data Use Conditions.

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

A global reference for human genetic variation.

The Matchmaker Exchange: a platform for rare disease gene discovery.

The UK10K project identifies rare variants in health and disease.

Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER.

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

Potential research participants support the return of raw sequence data.

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.

Copy number variation in the human Y chromosome in the UK population.

Mosaic structural variation in children with developmental disorders.

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.

No expectation to share incidental findings in genomic research.

Absence of heterozygosity due to template switching during replicative rearrangements.

Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling.

The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline.

Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes.

Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms.

Prenatal exome sequencing for fetuses with structural abnormalities: the next step.

Using population data for assessing next-generation sequencing performance.

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy.

Exome Sequencing in Fetuses with Structural Malformations.

Cis and trans effects of human genomic variants on gene expression.

Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.

Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.

De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability.

Rare variants in NR2F2 cause congenital heart defects in humans.

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders.

The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age.

Characterizing genetic variants for clinical action.

Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

Heterozygous loss-of-function mutations in YAP1 cause both isolated and syndromic optic fissure closure defects.

Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling.

Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures.

A genome-wide assessment of the role of untagged copy number variants in type 1 diabetes.

DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation.

Deletions of chromosomal regulatory boundaries are associated with congenital disease.

Extreme growth failure is a common presentation of ligase IV deficiency.

High throughput exome coverage of clinically relevant cardiac genes.

COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.

Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.

Reduced burden of very large and rare CNVs in bipolar affective disorder.

Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy.

DeNovoGear: de novo indel and point mutation discovery and phasing.

Cerebral organoids model human brain development and microcephaly.

TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.

Empirical research on the ethics of genomic research.

Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

NDUFA4 Mutations Underlie Dysfunction of a Cytochrome c Oxidase Subunit Linked to Human Neurological Disease.

Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice.

Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.

Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.

Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan.