Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes
Heather C. Mefford, M.D., Ph.D., Andrew J. Sharp, Ph.D., Carl Baker, B.S., Andy Itsara, B.A., Zhaoshi Jiang, M.D., Karen Buysse, M.S., Shuwen Huang, Ph.D., Viv K. Maloney, B.Sc., John A. Crolla, Ph.D., Diana Baralle, M.B., B.S., Amanda Collins, B.M., Catherine Mercer, B.M., Koen Norga, M.D., Ph.D., Thomy de Ravel, M.D., Koen Devriendt, M.D., Ph.D., Ernie M.H.F. Bongers, M.D., Ph.D., Nicole de Leeuw, Ph.D., William Reardon, M.D., Stefania Gimelli, Ph.D., Frederique Bena, Ph.D., Raoul C. Hennekam, M.D., Ph.D., Alison Male, M.R.C.P., Lorraine Gaunt, Ph.D., Jill Clayton-Smith, M.D., Ingrid Simonic, Ph.D., Soo Mi Park, M.B., B.S., Ph.D., Sarju G. Mehta, M.D., Serena Nik-Zainal, M.R.C.P., C. Geoffrey Woods, M.D., Helen V. Firth, D.M., Georgina Parkin, B.Sc., Marco Fichera, Ph.D., Santina Reitano, M.D., Mariangela Lo Giudice, B.S., Kelly E. Li, Ph.D., Iris Casuga, B.S., Adam Broomer, M.S., Bernard Conrad, M.D., Markus Schwerzmann, M.D., Lorenz Räber, M.D., Sabina Gallati, Ph.D., Pasquale Striano, M.D., Ph.D., Antonietta Coppola, M.D., John L. Tolmie, F.R.C.P., Edward S. Tobias, F.R.C.P., Chris Lilley, M.R.P.C.H., Lluis Armengol, Ph.D., Yves Spysschaert, M.D., Patrick Verloo, M.D., Anja De Coene, M.D., Linde Goossens, M.D., Geert Mortier, M.D., Ph.D., Frank Speleman, Ph.D., Ellen van Binsbergen, M.Sc., Marcel R. Nelen, Ph.D., Ron Hochstenbach, Ph.D., Martin Poot, Ph.D., Louise Gallagher, M.D., Ph.D., Michael Gill, M.D., Jon McClellan, M.D., Mary-Claire King, Ph.D., Regina Regan, Ph.D., Cindy Skinner, R.N., Roger E. Stevenson, M.D., Stylianos E. Antonarakis, M.D., Ph.D., Caifu Chen, Ph.D., Xavier Estivill, M.D., Ph.D., Björn Menten, Ph.D., Giorgio Gimelli, Ph.D., Susan Gribble, Ph.D., Stuart Schwartz, Ph.D., James S. Sutcliffe, Ph.D., Tom Walsh, Ph.D., Samantha J.L. Knight, Ph.D., Jonathan Sebat, Ph.D., Corrado Romano, M.D., Charles E. Schwartz, Ph.D., Joris A. Veltman, Ph.D., Bert B.A. de Vries, M.D., Ph.D., Joris R. Vermeesch, Ph.D., John C.K. Barber, Ph.D., Lionel Willatt, Ph.D., May Tassabehji, Ph.D., and Evan E. Eichler, Ph.D.
Background Duplications and deletions in the human genome cancause disease or predispose persons to disease. Advances intechnologies to detect these changes allow for the routine identificationof submicroscopic imbalances in large numbers of patients.
Methods We tested for the presence of microdeletions and microduplicationsat a specific region of chromosome 1q21.1 in two groups of patientswith unexplained mental retardation, autism, or congenital anomaliesand in unaffected persons.
Results We identified 25 persons with a recurrent 1.35-Mb deletionwithin 1q21.1 from screening 5218 patients. The microdeletionshad arisen de novo in eight patients, were inherited from amildly affected parent in three patients, were inherited froman apparently unaffected parent in six patients, and were ofunknown inheritance in eight patients. The deletion was absentin a series of 4737 control persons (P=1.1x10–7). We foundconsiderable variability in the level of phenotypic expressionof the microdeletion; phenotypes included mild-to-moderate mentalretardation, microcephaly, cardiac abnormalities, and cataracts.The reciprocal duplication was enriched in nine children withmental retardation or autism spectrum disorder and other variablefeatures (P=0.02). We identified three deletions and three duplicationsof the 1q21.1 region in an independent sample of 788 patientswith mental retardation and congenital anomalies.
Conclusions We have identified recurrent molecular lesions thatelude syndromic classification and whose disease manifestationsmust be considered in a broader context of development as opposedto being assigned to a specific disease. Clinical diagnosisin patients with these lesions may be most readily achievedon the basis of genotype rather than phenotype.
Source Information
The authors' affiliations are listed in the Appendix. Drs. Mefford and Sharp contributed equally to this article. This article (10.1056/NEJMoa0805384) was published at www.nejm.org on September 10, 2008.
Address reprint requests to Dr. Eichler at the Department of Genome Sciences, University of Washington and Howard Hughes Medical Institute, Foege Bldg. S413A, Box 355065, 1705 NE Pacific St., Seattle, WA 98195, or at eee{at}gs.washington.edu.
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