Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves.

1.
Barber JC: Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J Med Genet 42:609–629 (2005).
2.
Barber JCK, Maloney V, Hollox EJ, Stuke-Sontheimer A, du Bois G, et al: Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level. Eur J Hum Genet 13:1131–1136 (2005).
3.
Bonaglia MC, Giorda R, Carrozzo R, Roncoroni ME, Grasso R, et al: 20-Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: narrowing of the 9p duplication critical area to 6 Mb. Am J Med Genet 112:154–159 (2002).
4.
Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK: A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81 (2006).
5.
de Vries BBA, Pfundt R, Leisink M, Koolen DA, Vissers LELM, et al: Diagnostic genome profiling in mental retardation. Am J Hum Genet 77:606–616 (2005).
6.
Feuk L, Carson AR, Scherer SW: Structural variation in the human genome. Nat Rev Genet 7:85–97 (2006).
7.
Gardner RJM, Sutherland GR: Chromosome Abnormalities and Genetic Counselling. Third edition. (Oxford University Press, New York 2004).
8.
Hinds DA, Kloek AP, Jen M, Chen X, Frazer KA: Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat Genet 38:82–85 (2006).
9.
Hochstenbach R, van Amstel HKP, Poot M: Microarray-based genome investigation: molecular karyotyping or segmental aneuploidy profiling? Eur J Hum Genet 14:262–265 (2006).
10.
Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, et al: Detection of large-scale variation in the human genome. Nat Genet 36:949–951 (2004).
11.
Kriek M, White SJ, Szuhai K, Knijnenburg J, van Ommen G-JB, et al: Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications. Eur J Hum Genet 14:180–189 (2006).
12.
Lalani SR, Sahoo T, Sanders ME, Peters SU, Bejjani BA: Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2). BMC Med Genet 7:8 (2006).
13.
Lupski JR, Stankiewicz P: Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PloS Genet 1:e49 (2005).
14.
McCarroll SA, Hadnott TN, Perry GH, Sabeti PC, Zody MC, et al: Common deletion polymorphisms in the human genome. Nat Genet 38:86–92 (2006).
15.
Menten B, Maas N, Thienpont B, Buysse K, Vandesompele J, et al: Emerging patterns of cryptic chromosomal imbalances in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of the literature. J Med Genet 43:625–633 (2006).
16.
Portnoï M-F, Lebas F, Gruchy N, Ardalan A, Biran-Mucignat V, et al: 22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes. Am J Med Genet 137:47–51 (2005).
17.
Rosenberg C, Knijnenburg J, Bakker E, Vianna-Morgante AM, Sloos W, et al: Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. J Med Genet 43:180–186 (2006).
18.
Schotta G, Ebert A, Dorn R, Reuter G: Position-effect variegation and the genetic dissection of chromatin regulation in Drosophila. Semin Cell Dev Biol 14:67–75 (2003).
19.
Schoumans J, Ruivenkamp C, Holmberg E, Kyllerman M, Anderlid B-M, Nordenskjöld M: Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J Med Genet 42:699–705 (2005).
20.
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, et al: Large-scale copy number polymorphism in the human genome. Science 305:525–528 (2004).
21.
Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, et al: Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:78–88 (2005).
22.
Shaw CJ, Bi W, Lupski JR: Genetic proof of unequal crossovers in reciprocal deletion and duplication of 17p11.2. Am J Hum Genet 71:1072–1081 (2002).
23.
Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, et al: Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet 41:241–248 (2004).
24.
Vissers LELM, de Vries BBA, Osoegawa K, Janssen IM, Feuth T, et al: Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet 73:1261–1270 (2003).
25.
Wilson GN: Karyotype/phenotype controversy: Genetic and molecular implications of alternative hypotheses. Am J Hum Genet 36:500–505 (1990).
26.
Yobb TM, Somerville MJ, Willatt L, Firth HV, Harrison K, et al: Microduplication and triplication of 22q11.2: A highly variable syndrome. Am J Hum Genet 76:865–876 (2005).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.