Abstract
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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Acknowledgements
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.
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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.
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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.
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Girirajan, S., Rosenfeld, J., Cooper, G. et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 42, 203–209 (2010). https://doi.org/10.1038/ng.534
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DOI: https://doi.org/10.1038/ng.534
