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.

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We thank F. Hormozdiari, M. Dennis and T. Brown for useful discussions and for editing the manuscript. B.P.C. is supported by a fellowship from the Canadian Institutes of Health Research. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. J.A.R. and B.S.T. are employees of Signature Genomics Laboratories, LLC, a subsidiary of PerkinElmer, Inc. This work was supported by US National Institute of Mental Health grant MH101221 and Paul G. Allen Family Foundation Award 11631 to E.E.E. E.E.E. is an Allen Distinguished Investigator and an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Brian J O'Roak
    •  & Marco Fichera

    Present addresses: Molecular and Medical Genetics, Oregon Health and Science University (OHSU), Portland, Oregon, USA (B.J.O.) and Medical Genetics, University of Catania, Catania, Italy (M.F.).


  1. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

    • Bradley P Coe
    • , Kali Witherspoon
    • , Carl Baker
    • , Nik Krumm
    • , Brian J O'Roak
    • , Jay Shendure
    •  & Evan E Eichler
  2. Signature Genomics Laboratories, LLC, PerkinElmer, Inc., Spokane, Washington, USA.

    • Jill A Rosenfeld
    •  & Beth S Torchia
  3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Bregje W M van Bon
    • , Anneke T Vulto-van Silfhout
    • , Lisenka E L M Vissers
    • , Janneke H Schuurs-Hoeijmakers
    • , Alex Hoischen
    • , Rolph Pfundt
    • , Nicole de Leeuw
    • , Margot R F Reijnders
    • , Jayne Y Hehir-Kwa
    •  & Bert B A de Vries
  4. SA Pathology, North Adelaide, South Australia, Australia.

    • Bregje W M van Bon
    • , Kathryn L Friend
    • , Marie Shaw
    • , Elizabeth Thompson
    • , Eric Haan
    •  & Jozef Gécz
  5. IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy.

    • Paolo Bosco
    • , Serafino Buono
    • , Antonino Alberti
    • , Rosa Pettinato
    • , Marco Fichera
    •  & Corrado Romano
  6. Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Gemma L Carvill
    •  & Heather C Mefford
  7. Representing the Autism Phenome Project, MIND Institute, University of California, Davis, Sacramento, California, USA.

    • Deana Li
    •  & David Amaral
  8. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Natasha Brown
    •  & Paul J Lockhart
  9. Barwon Child Health Unit, Barwon Health, Geelong, Victoria, Australia.

    • Natasha Brown
  10. Murdoch Childrens Research Institute, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Paul J Lockhart
  11. Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Ingrid E Scheffer
  12. Division of Developmental and Behavioral Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.

    • Raymond Tervo
  13. Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

    • Hilde Peeters
  14. Leuven Autism Research (LAuRes), Leuven, Belgium.

    • Hilde Peeters
  15. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.

    • Elizabeth Thompson
    •  & Eric Haan
  16. Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.

    • Jozef Gécz
  17. Howard Hughes Medical Institute, Seattle, Washington, USA.

    • Evan E Eichler


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B.P.C. and E.E.E. designed the study. B.P.C. performed the data analysis. B.P.C., K.W. and C.B. performed array CGH, MIP sequencing and Sanger validation. J.A.R. and B.S.T. supervised array CGH experiments and coordinated clinical data collection at Signature Genomics. B.W.M.v.B., A.T.V.-v.S., P.B., K.L.F., S.B., L.E.L.M.V., J.H.S.-H., A.H., D.L., D.A., N.B., P.J.L., I.E.S., A.A., R. Pettinato, R.T., N.d.L., M.R.F.R., H.P., E.T., M.F., M.S., H.C.M., E.H., C.R., J.G. and B.B.A.d.V. provided clinical samples for resequencing, clinical reports and inheritance testing. J.Y.H.-K., R. Pfundt and N.d.L. curated the Nijmegen de novo CNV calls. B.P.C., K.W., C.B., B.J.O., J.S., and E.E.E. designed the MIP gene panel. G.L.C. and H.C.M. identified two SETBP1 variants in an independent screen. N.K. curated published de novo mutations. B.P.C. and E.E.E. wrote the manuscript. All authors have read and approved the final version of the manuscript.

Competing interests

J.A.R. and B.S.T. are employees of Signature Genomics Laboratories, LLC, a subsidiary of PerkinElmer, Inc. E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc., and was an SAB member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013).

Corresponding author

Correspondence to Evan E Eichler.

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    Supplementary Data Set 1

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