A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., Siswara, P., Itsara, A., Vives, L., Walsh, T., McCarthy, S. E., Baker, C., Mefford, H. C., Kidd, J. M., Browning, S. R., Browning, B. L., Dickel, D. E., Levy, D. L., Ballif, B. C., Platky, K., Farber, D. M., Gowans, G. C., Wetherbee, J. J., Asamoah, A., Weaver, D. D., Mark, P. R., Dickerson, J., Garg, B. P., Ellingwood, S. A., Smith, R., Banks, V. C., Smith, W., McDonald, M. T., Hoo, J. J., French, B. N., Hudson, C., Johnson, J. P., Ozmore, J. R., Moeschler, J. B., Surti, U., Escobar, L. F., El-Khechen, D., Gorski, J. L., Kussmann, J., Salbert, B., Lacassie, Y., Biser, A., McDonald-McGinn, D. M., Zackai, E. H., Deardorff, M. A., Shaikh, T. H., Haan, E., Friend, K. L., Fichera, M., Romano, C., Gécz, J., DeLisi, L. E., Sebat, J., King, M. C., Shaffer, L. G., Eichler, E. E. (2010) A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 42 (3). pp. 203-209.

URL: https://www.ncbi.nlm.nih.gov/pubmed/20154674
DOI: 10.1038/ng.534

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<sup>-5</sup>, 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.

Item Type: Paper
Uncontrolled Keywords: childhood developmental delay microdeletion 16p12.1 neuropsychiatric disease
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders > mental disorders
organism description > animal > developmental stage > child
organism description > animal > mammal > primates > hominids > human
CSHL Authors:
Communities: CSHL labs > McCombie lab
Depositing User: CSHL Librarian
Date Deposited: 30 Sep 2011 13:27
Last Modified: 02 Mar 2018 19:47
PMCID: PMC2847896
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15422

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