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

Publication ,  Journal Article
Girirajan, S; Rosenfeld, JA; Cooper, GM; Antonacci, F; Siswara, P; Itsara, A; Vives, L; Walsh, T; McCarthy, SE; Baker, C; Mefford, HC; Hoo, JJ ...
Published in: Nat Genet
March 2010

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.

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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2010

Volume

42

Issue

3

Start / End Page

203 / 209

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Recurrence
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Pedigree
  • Oligonucleotide Array Sequence Analysis
  • Models, Genetic
  • Infant
  • Humans
  • Gene Frequency
 

Citation

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Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., Siswara, P., Itsara, A., … Eichler, E. E. (2010). A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet, 42(3), 203–209. https://doi.org/10.1038/ng.534
Girirajan, Santhosh, Jill A. Rosenfeld, Gregory M. Cooper, Francesca Antonacci, Priscillia Siswara, Andy Itsara, Laura Vives, et al. “A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.Nat Genet 42, no. 3 (March 2010): 203–9. https://doi.org/10.1038/ng.534.
Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010 Mar;42(3):203–9.
Girirajan, Santhosh, et al. “A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.Nat Genet, vol. 42, no. 3, Mar. 2010, pp. 203–09. Pubmed, doi:10.1038/ng.534.
Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King M-C, Shaffer LG, Eichler EE. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010 Mar;42(3):203–209.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2010

Volume

42

Issue

3

Start / End Page

203 / 209

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Recurrence
  • Polymorphism, Single Nucleotide
  • Phenotype
  • Pedigree
  • Oligonucleotide Array Sequence Analysis
  • Models, Genetic
  • Infant
  • Humans
  • Gene Frequency