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

  • Author(s): 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
  • 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 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.

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