Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Girirajan S

PROVIDER: S-EPMC2847896 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Girirajan Santhosh S Rosenfeld Jill A JA Cooper Gregory M GM Antonacci Francesca F Siswara Priscillia P Itsara Andy A Vives Laura L Walsh Tom T McCarthy Shane E SE Baker Carl C Mefford Heather C HC Kidd Jeffrey M JM Browning Sharon R SR Browning Brian L BL Dickel Diane E DE Levy Deborah L DL Ballif Blake C BC Platky Kathryn K Farber Darren M DM Gowans Gordon C GC Wetherbee Jessica J JJ Asamoah Alexander A Weaver David D DD Mark Paul R PR Dickerson Jennifer J Garg Bhuwan P BP Ellingwood Sara A SA Smith Rosemarie R Banks Valerie C VC Smith Wendy W McDonald Marie T MT Hoo Joe J JJ French Beatrice N BN Hudson Cindy C Johnson John P JP Ozmore Jillian R JR Moeschler John B JB Surti Urvashi U Escobar Luis F LF El-Khechen Dima D Gorski Jerome L JL Kussmann Jennifer J Salbert Bonnie B Lacassie Yves Y Biser Alisha A McDonald-McGinn Donna M DM Zackai Elaine H EH Deardorff Matthew A MA Shaikh Tamim H TH Haan Eric E Friend Kathryn L KL Fichera Marco M Romano Corrado C Gécz Jozef J DeLisi Lynn E LE Sebat Jonathan J King Mary-Claire MC Shaffer Lisa G LG Eichler Evan E EE

Nature genetics 20100214 3

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). Proba ...[more]

PMID: 20154674

Similar Datasets

Project description:BackgroundRecent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown.MethodsWe performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and "second-hit" variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses.ResultsWe found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations in deletion carriers.ConclusionsOur results suggest a potential mechanism for how "second-hit" variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets