RT Journal Article
SR Electronic
T1 Prevalence, phenotype and architecture of developmental disorders caused by <em>de novo</em> mutation: The Deciphering Developmental Disorders Study
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 049056
DO 10.1101/049056
A1 Jeremy F McRae
A1 Stephen Clayton
A1 Tomas W Fitzgerald
A1 Joanna Kaplanis
A1 Elena Prigmore
A1 Diana Rajan
A1 AlejandroW Sifrim
A1 Stuart Aitken
A1 Nadia Akawi
A1 Mohsan Alvi
A1 Kirsty Ambridge
A1 Daniel M Barrett
A1 Tanya Bayzetinova
A1 Philip Jones
A1 Wendy D Jones
A1 Daniel King
A1 Netravathi Krishnappa
A1 Laura E Mason
A1 Tarjinder Singh
A1 Adrian R Tivey
A1 Munaza Ahmed
A1 Uruj Anjum
A1 Hayley Archer
A1 Ruth Armstrong
A1 Jana Awada
A1 Meena Balasubramanian
A1 Siddharth Banka
A1 Diana Baralle
A1 Angela Barnicoat
A1 Paul Batstone
A1 David Baty
A1 Chris Bennett
A1 Jonathan Berg
A1 Birgitta Bernhard
A1 A Paul Bevan
A1 Maria Bitner-Glindzicz
A1 Edward Blair
A1 Moira Blyth
A1 David Bohanna
A1 Louise Bourdon
A1 David Bourn
A1 Lisa Bradley
A1 Angela Brady
A1 Simon Brent
A1 Carole Brewer
A1 Kate Brunstrom
A1 David J Bunyan
A1 John Burn
A1 Natalie Canham
A1 Bruce Castle
A1 Kate Chandler
A1 Elena Chatzimichali
A1 Deirdre Cilliers
A1 Angus Clarke
A1 Susan Clasper
A1 Jill Clayton-Smith
A1 Virginia Clowes
A1 Andrea Coates
A1 Trevor Cole
A1 Irina Colgiu
A1 Amanda Collins
A1 Morag N Collinson
A1 Fiona Connell
A1 Nicola Cooper
A1 Helen Cox
A1 Lara Cresswell
A1 Gareth Cross
A1 Yanick Crow
A1 Mariella D'Alessandro
A1 Tabib Dabir
A1 Rosemarie Davidson
A1 Sally Davies
A1 Dylan de Vries
A1 John Dean
A1 Charu Deshpande
A1 Gemma Devlin
A1 Abhijit Dixit
A1 Angus Dobbie
A1 Alan Donaldson
A1 Dian Donnai
A1 Deirdre Donnelly
A1 Carina Donnelly
A1 Angela Douglas
A1 Sofia Douzgou
A1 Alexis Duncan
A1 Jacqueline Eason
A1 Sian Ellard
A1 Ian Ellis
A1 Frances Elmslie
A1 Karenza Evans
A1 Sarah Everest
A1 Tina Fendick
A1 Richard Fisher
A1 Frances Flinter
A1 Nicola Foulds
A1 AndrewW Fry
A1 Alan Fryer
A1 Carol Gardiner
A1 Lorraine Gaunt
A1 Neeti Ghali
A1 Richard Gibbons
A1 Harinder Gill
A1 Judith Goodship
A1 David Goudie
A1 Emma Gray
A1 Andrew Green
A1 Philip Greene
A1 Lynn Greenhalgh
A1 Susan Gribble
A1 Lucy Harrison
A1 Victoria Harrison
A1 Rose Hawkins
A1 Liu He
A1 Stephen Hellens
A1 Alex Henderson
A1 Sarah Hewitt
A1 Lucy Hildyard
A1 Emma Hobson
A1 Simon Holden
A1 Muriel Holder
A1 Susan Holder
A1 Georgina Hollingsworth
A1 Tessa Homfray
A1 Mervyn Humphreys
A1 Jane Hurst
A1 Ben Hutton
A1 Stuart Ingram
A1 Melita Irving
A1 Lily Islam
A1 Andrew Jackson
A1 Joanna Jarvis
A1 Lucy Jenkins
A1 Diana Johnson
A1 Elizabeth Jones
A1 Dragana Josifova
A1 Shelagh Joss
A1 Beckie Kaemba
A1 Sandra Kazembe
A1 Rosemary Kelsell
A1 Bronwyn Kerr
A1 Helen Kingston
A1 Usha Kini
A1 Esther Kinning
A1 Gail Kirby
A1 Claire Kirk
A1 Emma Kivuva
A1 Alison Kraus
A1 Dhavendra Kumar
A1 V.K Ajith Kumar
A1 Katherine Lachlan
A1 Wayne Lam
A1 Anne Lampe
A1 Caroline Langman
A1 Melissa Lees
A1 Derek Lim
A1 Cheryl Longman
A1 Gordon Lowther
A1 Sally A Lynch
A1 Alex Magee
A1 Eddy Maher
A1 Alison Male
A1 Sahar Mansour
A1 Karen Marks
A1 Katherine Martin
A1 Una Maye
A1 Emma McCann
A1 Vivienne McConnell
A1 Meriel McEntagart
A1 Ruth McGowan
A1 Kirsten McKay
A1 Shane McKee
A1 Dominic J McMullan
A1 Susan McNerlan
A1 Catherine McWilliam
A1 Sarju Mehta
A1 Kay Metcalfe
A1 Anna Middleton
A1 Zosia Miedzybrodzka
A1 Emma Miles
A1 Shehla Mohammed
A1 Tara Montgomery
A1 David Moore
A1 Sian Morgan
A1 Jenny Morton
A1 Hood Mugalaasi
A1 Victoria Murday
A1 Helen Murphy
A1 Swati Naik
A1 Andrea Nemeth
A1 Louise Nevitt
A1 Ruth Newbury-Ecob
A1 Andrew Norman
A1 Rosie O'Shea
A1 Caroline Ogilvie
A1 Kai-Ren Ong
A1 Soo-Mi Park
A1 Michael J Parker
A1 Chirag Patel
A1 Joan Paterson
A1 Stewart Payne
A1 Daniel Perrett
A1 Julie Phipps
A1 Daniela T Pilz
A1 Martin Pollard
A1 Caroline Pottinger
A1 Joanna Poulton
A1 Norman Pratt
A1 Katrina Prescott
A1 Sue Price
A1 Abigail Pridham
A1 Annie Procter
A1 Hellen Purnell
A1 Oliver Quarrell
A1 Nicola Ragge
A1 Raheleh Rahbari
A1 Josh Randall
A1 Julia Rankin
A1 Lucy Raymond
A1 Debbie Rice
A1 Leema Robert
A1 Eileen Roberts
A1 Jonathan Roberts
A1 Paul Roberts
A1 Gillian Roberts
A1 Alison Ross
A1 Elisabeth Rosser
A1 Anand Saggar
A1 Shalaka Samant
A1 Julian Sampson
A1 Richard Sandford
A1 Ajoy Sarkar
A1 Susann Schweiger
A1 Richard Scott
A1 Ingrid Scurr
A1 Ann Selby
A1 Anneke Seller
A1 Cheryl Sequeira
A1 Nora Shannon
A1 Saba Sharif
A1 Charles Shaw-Smith
A1 Emma Shearing
A1 Debbie Shears
A1 Eamonn Sheridan
A1 Ingrid Simonic
A1 Roldan Singzon
A1 Zara Skitt
A1 Audrey Smith
A1 Kath Smith
A1 Sarah Smithson
A1 Linda Sneddon
A1 Miranda Splitt
A1 Miranda Squires
A1 Fiona Stewart
A1 Helen Stewart
A1 Volker Straub
A1 Mohnish Suri
A1 Vivienne Sutton
A1 Ganesh Jawahar Swaminathan
A1 Elizabeth Sweeney
A1 Kate Tatton-Brown
A1 Cat Taylor
A1 Rohan Taylor
A1 Mark Tein
A1 I Karen Temple
A1 Jenny Thomson
A1 Marc Tischkowitz
A1 Susan Tomkins
A1 Audrey Torokwa
A1 Becky Treacy
A1 Claire Turner
A1 Peter Turnpenny
A1 Carolyn Tysoe
A1 Anthony Vandersteen
A1 Vinod Varghese
A1 Pradeep Vasudevan
A1 Parthiban Vijayarangakannan
A1 Julie Vogt
A1 Emma Wakeling
A1 Sarah Wallwark
A1 Jonathon Waters
A1 Astrid Weber
A1 Diana Wellesley
A1 Margo Whiteford
A1 Sara Widaa
A1 Sarah Wilcox
A1 Emily Wilkinson
A1 Denise Williams
A1 Nicola Williams
A1 Louise Wilson
A1 Geoff Woods
A1 Christopher Wragg
A1 Michael Wright
A1 Laura Yates
A1 Michael Yau
A1 Chris Nellaker
A1 Michael J Parker
A1 Helen V Firth
A1 Caroline F Wright
A1 David R FitzPatrick
A1 Jeffrey C Barrett
A1 Matthew E Hurles
YR 2016
UL http://biorxiv.org/content/early/2016/06/16/049056.abstract
AB Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P &lt; 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.PTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study