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

Mefford, H. C., Sharp, A. J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V. K., Crolla, J. A., Baralle, D., Collins, A., Mercer, C., Norga, K., de Ravel, T., Devriendt, K., Bongers, E. M., de Leeuw, N., Reardon, W., Gimelli, S., Bena, F., Hennekam, R. C., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S. M., Mehta, S. G., Nik-Zainal, S., Woods, C. G., Firth, H. V., Parkin, G., Fichera, M., Reitano, S., Lo Giudice, M., Li, K. E., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Raber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J. L., Tobias, E. S., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., De Coene, A., Goossens, L., Mortier, G., Speleman, F., van Binsbergen, E., Nelen, M. R., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., McClellan, J., King, M. C., Regan, R., Skinner, C., Stevenson, R. E., Antonarakis, S. E., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S., Schwartz, S., Sutcliffe, J. S., Walsh, T., Knight, S. J., Sebat, J., Romano, C., Schwartz, C. E., Veltman, J. A., de Vries, B. B., Vermeesch, J. R., Barber, J. C., Willatt, L., Tassabehji, M., Eichler, E. E. (October 2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. New England Journal of Medicine , 359 (16). pp. 1685-99.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18784092
DOI: 10.1056/NEJMoa0805384

Abstract

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=1.1x10(-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.

Item Type: Paper
Uncontrolled Keywords: Autistic Disorder/*genetics Cataract/congenital/genetics Child *Chromosome Aberrations Chromosome Deletion Chromosomes, Human, Pair 1/*genetics Congenital Abnormalities/*genetics Female Gene Duplication Gene Rearrangement Heart Defects, Congenital/genetics Humans Male Mental Retardation/*genetics Microcephaly/genetics Phenotype Recombination, Genetic Variation (Genetics)
Subjects: bioinformatics
diseases & disorders > congenital hereditary genetic diseases
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > mental disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
diseases & disorders > congenital hereditary genetic diseases > mental retardation
CSHL Authors:
Communities: CSHL labs > Sebat lab
Depositing User: Matt Covey
Date: 16 October 2008
Date Deposited: 25 Feb 2013 20:46
Last Modified: 25 Feb 2013 20:46
PMCID: PMC2703742
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27603

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