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

  • Author(s): 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, MC
  • Shaffer, LG
  • Eichler, EE
  • et al.

Published Web Location

https://doi.org/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 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. © 2010 Nature America, Inc. All rights reserved.

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