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Exclusion mapping of the X-linked dominant chondrodysplasia punctata/ichthyosis/cataract/short stature (Happle) syndrome: possible involvement of an unstable pre-mutation

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Summary

Homology with the mouse bare patches mutant suggests that the gene for the X-linked dominant chondrodysplasia punctata / ichthyosis / cataract / short stature syndrome (Happle syndrome) is located in the human Xq28 region. To test this hypothesis, we performed a linkage study in three families comprising a total of 12 informative meioses. Multiple recombinations appear to exclude the Xq28 region as the site of the gene. Surprisingly, multiple crossovers were also found with 26 other markers spread along the rest of the X chromosome. Two-point linkage analysis and analysis of recombination chromosomes seem to exclude the gene from the entire X chromosome. Three different mechanisms are discussed that could explain the apparent exclusion of an X-linked gene from the X chromosome by linkage analysis: (a) different mutations on the X chromosome disturbing X inactivation, (b) metabolic interference, i.e. allele incompatibility of an X-linked gene, and (c) an unstable pre-mutation that can become silent in males. We favour the last explanation, as it would account for the unexpected sex ratio (M∶F) of 1.2∶1 among surviving siblings, and for the striking clinical variability of the phenotype, including stepwise increases in disease expression in successive generations.

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Authors and Affiliations

  1. Department of Human Genetics, University Hospital, P.O. Box 9101, NL-6500, Nijmegen, HB, The Netherlands

    Heiko Traupe, Frans P. M. Cremers, Bernard A. van Oost & Hans-Hilger Ropers

  2. Hospital for Sick Infants and Center for Clinical Genetics, Municipal Hospitals, Flemmingstrasse 4, O-9091, Chemnitz, Federal Republic of Germany

    Dietmar Müller

  3. Pediatric Dermatology Unit, The Hospitals for Sick Children, Great Ormond Street, WC1N 3JH, London, UK

    David Atherton

  4. Department of Dermatology, Walter Reed Army Medical Center, Washington, DC, USA

    D. Chester Kalter

Authors
  1. Heiko Traupe
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  2. Dietmar Müller
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  3. David Atherton
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  4. D. Chester Kalter
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  5. Frans P. M. Cremers
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  6. Bernard A. van Oost
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  7. Hans-Hilger Ropers
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Traupe, H., Müller, D., Atherton, D. et al. Exclusion mapping of the X-linked dominant chondrodysplasia punctata/ichthyosis/cataract/short stature (Happle) syndrome: possible involvement of an unstable pre-mutation. Hum Genet 89, 659–665 (1992). https://doi.org/10.1007/BF00221958

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  • DOI: https://doi.org/10.1007/BF00221958

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