A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.
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.
Girirajan, S; Rosenfeld, JA; Cooper, GM; Antonacci, F; Siswara, P; Itsara, A; Vives, L; Walsh, T; McCarthy, SE; Baker, C; Mefford, HC; Kidd, JM; Browning, SR; Browning, BL; Dickel, DE; Levy, DL; Ballif, BC; Platky, K; Farber, DM; Gowans, GC; Wetherbee, JJ; Asamoah, A; Weaver, DD; Mark, PR; Dickerson, J; Garg, BP; Ellingwood, SA; Smith, R; Banks, VC; Smith, W; McDonald, MT; Hoo, JJ; French, BN; Hudson, C; Johnson, JP; Ozmore, JR; Moeschler, JB; Surti, U; Escobar, LF; El-Khechen, D; Gorski, JL; Kussmann, J; Salbert, B; Lacassie, Y; Biser, A; McDonald-McGinn, DM; Zackai, EH; Deardorff, MA; Shaikh, TH; Haan, E; Friend, KL; Fichera, M; Romano, C; Gécz, J; DeLisi, LE; Sebat, J; King, M-C; Shaffer, LG; Eichler, EE
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