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

Nat Genet 2010 Mar 14;42(3):203-9. Epub 2010 Feb 14.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847896PMC
March 2010
70 Reads

Publication Analysis

Top Keywords

two-hit model
12
16p121 microdeletion
12
cases compared
8
neuropsychiatric phenotypes
8
developmental delay
8
0037 probands
4
parents 0037
4
large deletions
4
probands carry
4
large copy-number
4
neurodevelopmental phenotypes
4
additional large
4
carry additional
4
non-carrier parents
4
phenotypes association
4
association large
4
phenotypes compared
4
duplications analysis
4
deletions inherited
4
support two-hit
4

Similar Publications