Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes

H. Mefford, A. Sharp, C. Baker, A. Itsara, Z. Jiang, K. Buysse, S. Huang, V. Maloney, J. Crolla, D. Baralle, A. Collins, C. Mercer, K. Norga, T. De Ravel, K. Devriendt, E. Bongers, N. De Leeuw, W. Reardon, S. Gimelli, F. BenaR. Hennekam, A. Male, L. Gaunt, J. Clayton-Smith, I. Simonic, S. Park, S. Mehta, S. Nik-Zainal, C. Woods, H. Firth, G. Parkin, M. Fichera, S. Reitano, M. Lo Giudice, K. Li, I. Casuga, A. Broomer, B. Conrad, M. Schwerzmann, L. Räber, S. Gallati, P. Striano, A. Coppola, J. Tolmie, E. Tobias, C. Lilley, L. Armengol, Y. Spysschaert, P. Verloo, A. De Coene, L. Goossens, G. Mortier, F. Speleman, E. Van Binsbergen, M. Nelen, R. Hochstenbach, M. Poot, L. Gallagher, M. Gill, J. McClellan, M. C. King, R. Regan, C. Skinner, R. Stevenson, S. Antonarakis, C. Chen, X. Estivill, B. Menten, G. Gimelli, S. Gribble, S. Schwartz, J. Sutcliffe, T. Walsh, S. Knight, J. Sebat, C. Romano, C. Schwartz, J. Veltman, B. De Vries, J. Vermeesch, J. Barber, L. Willatt, M. Tassabehji, E. Eichler

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P = 1.1×10-7). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P = 0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.

Original languageEnglish
Pages (from-to)1685-1699
Number of pages15
JournalNew England Journal of Medicine
Issue number16
Publication statusPublished - Oct 16 2008

ASJC Scopus subject areas

  • Medicine(all)


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