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

Santhosh Girirajan, Jill A. Rosenfeld, Gregory M. Cooper, Francesca Antonacci, Priscillia Siswara, Andy Itsara, Laura Vives, Tom Walsh, Shane E. McCarthy, Carl Baker, Heather C. Mefford, Jeffrey M. Kidd, Sharon R. Browning, Brian L. Browning, Diane E. Dickel, Deborah L. Levy, Blake C. Ballif, Kathryn Platky, Darren M. Farber, Gordon C. GowansJessica J. Wetherbee, Alexander Asamoah, David D. Weaver, Paul R. Mark, Jennifer Dickerson, Bhuwan P. Garg, Sara A. Ellingwood, Rosemarie Smith, Valerie C. Banks, Wendy Smith, Marie T. McDonald, Joe J. Hoo, Beatrice N. French, Cindy Hudson, John P. Johnson, Jillian R. Ozmore, John B. Moeschler, Urvashi Surti, Luis F. Escobar, Dima El-Khechen, Jerome L. Gorski, Jennifer Kussmann, Bonnie Salbert, Yves Lacassie, Alisha Biser, Donna M. McDonald-Mcginn, Elaine H. Zackai, Matthew A. Deardorff, Tamim H. Shaikh, Eric Haan, Kathryn L. Friend, Marco Fichera, Corrado Romano, Jozef Gécz, Lynn E. Delisi, Jonathan Sebat, Mary Claire King, Lisa G. Shaffer, Evan E. Eichler

Research output: Contribution to journalArticlepeer-review

487 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)203-209
Number of pages7
JournalNature Genetics
Issue number3
StatePublished - Mar 2010

All Science Journal Classification (ASJC) codes

  • Genetics


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