Santhosh Girirajan 1 , Jill A. Rosenfeld 2 , Gregory M. Cooper 1 , Francesca Antonacci 1 , Priscillia Siswara 1 , Andy Itsara 1 , Laura Vives 1 , Tom Walsh 3 , Shane E. McCarthy 4 , Carl Baker 1 , Heather C. Mefford 1 , Jeffrey M. Kidd 1 , Sharon R. Browning 5 , Brian L. Browning 5 , Diane E. Dickel 1 , Deborah L. Levy 6 , 7 , Blake C. Ballif 2 , Kathryn Platky 8 , Darren M. Farber 8 , Gordon C. Gowans 9 , Jessica J. Wetherbee 9 , Alexander Asamoah 9 , David D. Weaver 10 , Paul R. Mark 10 , Jennifer Dickerson 11 , Bhuwan P. Garg 11 , Sara A. Ellingwood 12 , Rosemarie Smith 12 , Valerie C. Banks 12 , Wendy Smith 12 , Marie T. McDonald 13 , Joe J. Hoo 14 , Beatrice N. French 14 , Cindy Hudson 15 , John P. Johnson 15 , Jillian R. Ozmore 16 , John B. Moeschler 16 , Urvashi Surti 17 , Luis F. Escobar 18 , Dima El-Kechen 18 , Jerome L. Gorski 19 , Jennifer Kussman 19 , Bonnie Salbert 20 , Yves Lacassie 21 , Alisha Biser 22 , Donna M. McDonald-McGinn 22 , Elaine H. Zackai 22 , Matthew A. Deardorff 22 , Tamim H. Shaikh 22 , Eric Haan 23 , 24 , Kathryn L. Friend 25 , Marco Fichera 26 , Corrado Romano 26 , Jozef Gécz 24 , 25 , Lynn E. deLisi 27 , 28 , Jonathan Sebat 29 , Mary-Claire King 1 , 3 , Lisa G. Shaffer 2 , Evan E. Eichler 1 , 30
14 February 2010
We report the identification of a recurrent 520-kbp 16p12.1 microdeletion significantly associated with childhood developmental delay. The microdeletion was detected in 20/11,873 cases vs. 2/8,540 controls ( p=0.0009, OR=7.2) and replicated in a second series of 22/9,254 cases vs. 6/6,299 controls ( p=0.028, OR=2.5). Most deletions were inherited with carrier parents likely to manifest neuropsychiatric phenotypes ( p=0.037, OR=6). Probands were more likely to carry an additional large CNV when compared to matched controls (10/42 cases, p=5.7×10 -5, OR=6.65). Clinical features of cases with two mutations were distinct from and/or more severe than clinical features of patients carrying only the co-occurring mutation. Our data suggest 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 suggests that this two-hit model may be more generally applicable to neuropsychiatric disease.