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Molecular mechanism for duplication 17p11.2— the homologous recombination reciprocal of the Smith-Magenis microdeletion

Abstract

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders1. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A–REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion5,6,7. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.

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Figure 1: Two-colour FISH analysis using PMP22, FLII and ZNF179 probes.
Figure 2: PFGE detection of novel 17p11.2 duplication junction fragments.
Figure 3: Haplotypes of seven duplication patients and their parents.
Figure 4

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Acknowledgements

We thank the patients and their families for participation, and A.L. Beaudet and S.M. Rosenberg for reviewing the manuscript. This work was supported in part by grants from the National Institute of Child Health and Development (NIH, K08HD01149; L.P.), the National Cancer Institute (P01CA75719; J.R.L.), the Baylor College of Medicine Mental Retardation Research Center (HD2406402), the Baylor Child Health Research Center (HD94021) and the Texas Children's Hospital General Clinical Research Center (M01RR00188).

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Correspondence to James R. Lupski.

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Potocki, L., Chen, KS., Park, SS. et al. Molecular mechanism for duplication 17p11.2— the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 24, 84–87 (2000). https://doi.org/10.1038/71743

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