title: Refining analyses of copy number variation identifies specific genes associated with developmental delay.
abstract: Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Witherspoon
authors.affiliation: Signature Genomics Laboratories, LLC, PerkinElmer, Inc., Spokane, Washington, USA.
authors.forename: Jill A
authors.identifier: 0000000156647987
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. [2] SA Pathology, North Adelaide, South Australia, Australia.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bosco
authors.affiliation: SA Pathology, North Adelaide, South Australia, Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Friend
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.affiliation: IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Serafino
authors.initials: S
authors.lastname: Buono
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Janneke H
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Nik
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.affiliation: Representing the Autism Phenome Project, MIND Institute, University of California, Davis, Sacramento, California, USA.
authors.forename: Deana
authors.initials: D
authors.lastname: Li
authors.affiliation: Representing the Autism Phenome Project, MIND Institute, University of California, Davis, Sacramento, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Amaral
authors.affiliation: 1] Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. [2] Barwon Child Health Unit, Barwon Health, Geelong, Victoria, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Brown
authors.affiliation: 1] Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. [2] Murdoch Childrens Research Institute, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Paul J
authors.identifier: 0000000325318413
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Alberti
authors.affiliation: SA Pathology, North Adelaide, South Australia, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Pettinato
authors.affiliation: Division of Developmental and Behavioral Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Tervo
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Margot R F
authors.identifier: 0000000263797147
authors.initials: MR
authors.lastname: Reijnders
authors.affiliation: Signature Genomics Laboratories, LLC, PerkinElmer, Inc., Spokane, Washington, USA.
authors.forename: Beth S
authors.initials: BS
authors.lastname: Torchia
authors.affiliation: 1] Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. [2] Leuven Autism Research (LAuRes), Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Peeters
authors.affiliation: 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2].
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: 1] IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy. [2].
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: 1] SA Pathology, North Adelaide, South Australia, Australia. [2] School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: 1] SA Pathology, North Adelaide, South Australia, Australia. [2] Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jozef
authors.identifier: 0000000278846861
authors.initials: J
authors.lastname: Gécz
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.affiliation: 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, Seattle, Washington, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002648:Child; D002874:Chromosome Mapping; D056970:Co-Repressor Proteins; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human; C094763:ZMYND11 protein, human