A recurrent 16p12.1 microdeletion suggests a two-hit model for severe developmental delay
By S. Girirajan, J. Rosenfeld, Gregory M. Cooper, F. Antonacci, P. Siswara, A. Itsara, Laura Vives, T. Walsh, S. McCarthy, Carl A. Baker and 49 more. Nature Genetics, 2010
596 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/34ef434afd565f9558e02873c28042bbb53b036b
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Citations in the corpus
- Characterising and Predicting Haploinsufficiency in the Human Genome (2010, background): “It has recently been suggested that some developmental disorders result from the presence of two independent deletions in the same genome, the ‘two-hit’ hypothesis”
- Autism risk factors: genes, environment, and gene-environment interactions (2012, background): “A first hypothesis to explain this phenotypic heterogeneity is that a secondary insult is necessary during development to result in the phenotype, as in the “twohit model” proposed in developmental delay.(48) Several studies recently supported the existence of such a combination of rare variants in ”