A Recurrent 16p12.1 Microdeletion Supports a Two-hit Model for Severe Developmental Delay

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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References

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

Helbig I, Mefford H, Sharp A, Guipponi M, Fichera M, Franke A . 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009; 41(2):160-2. PMC: 3026630. DOI: 10.1038/ng.292. View

Phelan M, Rogers R, Saul R, Stapleton G, Sweet K, McDermid H . 22q13 deletion syndrome. Am J Med Genet. 2001; 101(2):91-9. DOI: 10.1002/1096-8628(20010615)101:2<91::aid-ajmg1340>3.0.co;2-c. View

Xu B, Roos J, Levy S, van Rensburg E, Gogos J, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008; 40(7):880-5. DOI: 10.1038/ng.162. View

Marques-Bonet T, Girirajan S, Eichler E . The origins and impact of primate segmental duplications. Trends Genet. 2009; 25(10):443-54. PMC: 2847396. DOI: 10.1016/j.tig.2009.08.002. View

Mefford H, Eichler E . Duplication hotspots, rare genomic disorders, and common disease. Curr Opin Genet Dev. 2009; 19(3):196-204. PMC: 2746670. DOI: 10.1016/j.gde.2009.04.003. View

Ballif B, Hornor S, Jenkins E, Madan-Khetarpal S, Surti U, Jackson K . Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet. 2007; 39(9):1071-3. DOI: 10.1038/ng2107. View

Loftus B, Kim U, Sneddon V, Kalush F, Brandon R, Fuhrmann J . Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q. Genomics. 1999; 60(3):295-308. DOI: 10.1006/geno.1999.5927. View

Stefansson H, Rujescu D, Cichon S, Pietilainen O, Ingason A, Steinberg S . Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455(7210):232-6. PMC: 2687075. DOI: 10.1038/nature07229. View

10.

Mao X, Orchard G, Lillington D, Russell-Jones R, Young B, Whittaker S . Genetic alterations in primary cutaneous CD30+ anaplastic large cell lymphoma. Genes Chromosomes Cancer. 2003; 37(2):176-85. DOI: 10.1002/gcc.10184. View

11.

DeLisi L, Mesen A, Rodriguez C, Bertheau A, Laprade B, Llach M . Clinical characteristics of schizophrenia in multiply affected Spanish origin families from Costa Rica. Psychiatr Genet. 2001; 11(3):145-52. DOI: 10.1097/00041444-200109000-00006. View

12.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

13.

. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455(7210):237-41. PMC: 3912847. DOI: 10.1038/nature07239. View

14.

Lindgren V, Bryke C, Ozcelik T, Yang-Feng T, Francke U . Phenotypic, cytogenetic, and molecular studies of three patients with constitutional deletions of chromosome 5 in the region of the gene for familial adenomatous polyposis. Am J Hum Genet. 1992; 50(5):988-97. PMC: 1682619. View

15.

Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada K, Holmans P . Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet. 2009; 18(8):1497-503. PMC: 2664144. DOI: 10.1093/hmg/ddp043. View

16.

Fombonne E . Epidemiological trends in rates of autism. Mol Psychiatry. 2002; 7 Suppl 2:S4-6. DOI: 10.1038/sj.mp.4001162. View

17.

Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, Rosenberg C . Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat. 2007; 28(7):674-82. DOI: 10.1002/humu.20546. View

18.

Hannes F, Sharp A, Mefford H, de Ravel T, Ruivenkamp C, Breuning M . Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet. 2008; 46(4):223-32. PMC: 2658752. DOI: 10.1136/jmg.2007.055202. View

19.

Zhang F, Gu W, Hurles M, Lupski J . Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009; 10:451-81. PMC: 4472309. DOI: 10.1146/annurev.genom.9.081307.164217. View

20.

Johnson M, Cheng Z, Morrison V, Scherer S, Ventura M, Gibbs R . Recurrent duplication-driven transposition of DNA during hominoid evolution. Proc Natl Acad Sci U S A. 2006; 103(47):17626-31. PMC: 1693797. DOI: 10.1073/pnas.0605426103. View