We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10−5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

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We thank the subjects and their families for participating in this study. We thank M. Whyte for providing cardiological evaluation (for case SG07). We thank A. Singleton, L. Ferrucci and R. Krauss for sharing the control CNV data generated with support from the Intramural Research Program of the National Institute on Aging, National Heart, Lung, and Blood Institute (PARC project), and the National Institutes of Health, Department of Health and Human Services. For the schizophrenia study, genotyping of samples was also provided through the genetic association information network (GAIN). Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator: P.V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA). We also thank J. Smith for SNP genotyping; T. Louie for bioinformatics support; C. Campbell, L. Perez-Jurado, G. Kirov, M.K. Rudd and C. Lese-Martin for useful discussions; and T. Brown, P. Sudmant and J. Kitzman for critical review of the manuscript. This work was supported by NIH grant HD065285 (E.E.E.), a grant from the Simons Foundation (SFARI 137578 to E.E.E.) and a NARSAD Award (M.-C.K.). G.M.C. is supported by a Merck, Jane Coffin Childs Memorial Fund post-doctoral fellowship. E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Santhosh Girirajan
    •  & Jill A Rosenfeld

    These authors contributed equally to this work.


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

    • Santhosh Girirajan
    • , Gregory M Cooper
    • , Francesca Antonacci
    • , Priscillia Siswara
    • , Andy Itsara
    • , Laura Vives
    • , Carl Baker
    • , Heather C Mefford
    • , Jeffrey M Kidd
    • , Diane E Dickel
    • , Mary-Claire King
    •  & Evan E Eichler
  2. Signature Genomic Laboratories, Spokane, Washington, USA.

    • Jill A Rosenfeld
    • , Blake C Ballif
    •  & Lisa G Shaffer
  3. Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

    • Tom Walsh
    •  & Mary-Claire King
  4. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

    • Shane E McCarthy
  5. Department of Statistics, Faculty of Science, The University of Auckland, Auckland, New Zealand.

    • Sharon R Browning
    •  & Brian L Browning
  6. Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts, USA.

    • Deborah L Levy
  7. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

    • Deborah L Levy
    •  & Lynn E DeLisi
  8. Weisskopf Child Evaluation Center, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA.

    • Kathryn Platky
    • , Gordon C Gowans
    • , Jessica J Wetherbee
    •  & Alexander Asamoah
  9. Division of Child Neurology, Department of Neurology, University of Louisville, School of Medicine, Louisville, Kentucky, USA.

    • Darren M Farber
  10. Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.

    • David D Weaver
    •  & Paul R Mark
  11. Department of Neurology, Division of Pediatric Neurology, School of Medicine, Indiana University, Indianapolis, Indiana, USA.

    • Jennifer Dickerson
    •  & Bhuwan P Garg
  12. Division of Genetics, Maine Medical Partners Pediatric Specialty Care, Maine Medical Center, Portland, Maine, USA.

    • Sara A Ellingwood
    • , Rosemarie Smith
    • , Valerie C Banks
    •  & Wendy Smith
  13. Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.

    • Marie T McDonald
  14. Department of Pediatrics, University of Toledo Medical College and Northwest Ohio Regional Genetics Center, Toledo, Ohio, USA.

    • Joe J Hoo
    •  & Beatrice N French
  15. Medical Genetics, Shodair Children's Hospital, Helena, Montana, USA.

    • Cindy Hudson
    •  & John P Johnson
  16. Division of Clinical Genetics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.

    • Jillian R Ozmore
    •  & John B Moeschler
  17. Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

    • Urvashi Surti
  18. Medical Genetics and Neurodevelopmental Center, St. Vincent Children's Hospital, Indianapolis, Indiana, USA.

    • Luis F Escobar
    •  & Dima El-Khechen
  19. Division of Medical Genetics, University of Missouri, Columbia, Missouri, USA.

    • Jerome L Gorski
    •  & Jennifer Kussmann
  20. Geisinger Medical Center, Danville, Pennsylvania, USA.

    • Bonnie Salbert
  21. Division of Genetics, Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, Louisiana, USA.

    • Yves Lacassie
  22. Department of Pediatrics and Genetics, University of Pennsylvania, and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Alisha Biser
    • , Donna M McDonald-McGinn
    • , Elaine H Zackai
    • , Matthew A Deardorff
    •  & Tamim H Shaikh
  23. South Australian Clinical Genetics Service, South Australian Pathology at Women's and Children's Hospital, Adelaide, Australia.

    • Eric Haan
  24. Department of Paediatrics, The University of Adelaide, Adelaide, Australia.

    • Eric Haan
    •  & Jozef Gécz
  25. Genetics and Molecular Pathology, and South Australian Pathology at Women's and Children's Hospital, Adelaide, Australia.

    • Kathryn L Friend
    •  & Jozef Gécz
  26. Oasi Institute for Research and Care in Mental Retardation and Brain Aging, Troina, Italy.

    • Marco Fichera
    •  & Corrado Romano
  27. VA Boston Healthcare System, Brockton, Massachusetts, USA.

    • Lynn E DeLisi
  28. Departments of Psychiatry and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.

    • Jonathan Sebat
  29. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

    • Evan E Eichler


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This study was designed by S.G., L.G.S. and E.E.E. J.A.R., B.C.B. and L.G.S. supervised array-CGH experiments at Signature Genomics. J.A.R. coordinated clinical data collection. T.W., S.E.M., D.E.D., D.L.L., J.S., L.E.D. and M.-C.K. contributed to schizophrenia data collection and analysis. S.G., L.V. and C.B. performed high-density array-CGH experiments. G.M.C. and A.I. analyzed control CNV data. S.G., F.A. and J.M.K. performed genome structure analysis. F.A. performed FISH experiments. S.G. and P.S. sequenced and analyzed candidate genes. S.R.B. and B.L.B. performed haplotype analysis. K.P., D.M.F., G.C.G., J.J.W., A.A., D.D.W., P.R.M., J.D., B.P.G., S.A.E., R.S., V.C.B., W.S., M.T.M., J.J.H., B.N.F., C.H., J.P.J., J.R.O., J.B.M., U.S., L.F.E., D.E.-K., J.L.G., J.K., B.S., Y.L., A.B., D.M.M.-M., E.H.Z., M.A.D., T.H.S., E.H., K.L.F., M.F., C.R. and J.G. provided clinical information. H.C.M. provided 1q21.1 data. S.G., G.M.C., M.-C.K. and E.E.E. contributed to data interpretation. S.G. and E.E.E. wrote the manuscript.

Competing interests

E.E.E. is a member of the Scientific Advisory Board of Pacific Biosciences. J.A.R. and B.C.B. are employees of Signature Genomic Laboratories, LLC. L.G.S. is an employee of, owns shares in and sits on the Members' Board of Signature Genomic Laboratories, LLC.

Corresponding author

Correspondence to Evan E Eichler.

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