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- Title
A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.
- Authors
Girirajan, Santhosh; Rosenfeld, Jill A; Cooper, Gregory M; Antonacci, Francesca; Siswara, Priscillia; Itsara, Andy; Vives, Laura; Walsh, Tom; McCarthy, Shane E; Baker, Carl; Mefford, Heather C; Kidd, Jeffrey M; Browning, Sharon R; Browning, Brian L; Dickel, Diane E; Levy, Deborah L; Ballif, Blake C; Platky, Kathryn; Farber, Darren M; Gowans, Gordon C; Wetherbee, Jessica J; Asamoah, Alexander; Weaver, David D; Mark, Paul R; Dickerson, Jennifer; Garg, Bhuwan P; Ellingwood, Sara A; Smith, Rosemarie; Banks, Valerie C; Smith, Wendy; McDonald, Marie T; Hoo, Joe J; French, Beatrice N; Hudson, Cindy; Johnson, John P; Ozmore, Jillian R; Moeschler, John B; Surti, Urvashi; Escobar, Luis F; El-Khechen, Dima; Gorski, Jerome L; Kussmann, Jennifer; Salbert, Bonnie; Lacassie, Yves; Biser, Alisha; McDonald-McGinn, Donna M; Zackai, Elaine H; Deardorff, Matthew A; Shaikh, Tamim H; Haan, Eric; Friend, Kathryn L; Fichera, Marco; Romano, Corrado; Gécz, Jozef; DeLisi, Lynn E; Sebat, Jonathan; King, Mary-Claire; Shaffer, Lisa G; Eichler, Evan E
- 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 x 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.
- Publication
Nature genetics, 2010, Vol 42, Issue 3, p203
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.534