Journal Article

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

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

2010

Overview

Evan Eichler and colleagues identify a recurrent microdeletion on 16p12.1 associated with developmental, cognitive and neuropsychiatric phenotypes. They also show that more severe phenotypes are frequently correlated with the presence of a second large genomic rearrangement, supporting a complex model of pathogenesis that may underlie the variable expressivity typical of many microdeletion syndromes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212/748 / 631/208/727/2000 / 631/208/737 / 631/378/1689/2608 / Adult / Agriculture / Animal Genetics and Genomics / Artificial chromosomes / Autism / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Case-Control Studies / Child / Child, Preschool / Chromosome Deletion / Chromosomes, Human, Pair 16 - genetics / Comparative Genomic Hybridization - methods / Developmental delay / Developmental Disabilities - genetics / Disability / Experiments / Family / Fundamental and applied biological sciences. Psychology / Gene Frequency / Gene Function / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Human Genetics / Humans / Infant / Models, Genetic / Mutation / Oligonucleotide Array Sequence Analysis / Pedigree / Phenotype / Polymorphism, Single Nucleotide / Recurrence / Severity of Illness Index