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

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

    Research output: Contribution to journalArticlepeer-review

    473 Citations (Scopus)


    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
    Pages (from-to)203-209
    Number of pages7
    JournalNature Genetics
    Issue number3
    Publication statusPublished - Mar 2010


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