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. (March 2010) A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 42 (3). pp. 203-209.
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: | March 2010 |
| Date Deposited: | 30 Sep 2011 13:27 |
| Last Modified: | 02 Mar 2018 19:47 |
| PMCID: | PMC2847896 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15422 |
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