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

• DOI: 10.1038/ng.534
• Publication Date: 2010-02-14T18:10:01Z
• Authors: 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 Gowans; Jessica 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-...; 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
• Keywords: Adult; 572; Agricultural Biotechnology; Developmental Disabilities; Agricultural biotechnology; Bioinformatics and Computational Biology; Veterinary and Food Sciences; Medical and Health Sciences; Polymorphism, Single Nucleotide; Severity of Illness Index; Chromosomes; Article; Genetic; Gene Frequency; Models; Recurrence; Genetics; 2.1 Biological and endogenous factors; Humans; Family; Aetiology; Polymorphism; Preschool; Child; Oligonucleotide Array Sequence Analysis; Pediatric; Agricultural; Comparative Genomic Hybridization; Models, Genetic; Pair 16; Neurosciences; Infant; Single Nucleotide; Biological Sciences; Bioinformatics and computational biology; Brain Disorders; Pedigree; 3. Good health; Phenotype; Case-Control Studies; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 16; Human; Developmental Biology

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.