Abstract for presentation at 11th International Congress of Human Genetics

Disease-related gene duplications: more common than expected?

  • Marijke Bauters, Human Genome Laboratory, Flanders Interuniversity institute for Biotechnology (VIB4), Dept. Human Genetics, University of Leuve, Belgium
  • Hilde Van Esch, University Hospital Leuven, Dept. Human Genetics, University of Leuven, Belgium
  • Jean-Pierre Fryns, University Hospital Leuven, Dept. Human Genetics, University of Leuven, Belgium
  • Peter Marynen, Human Genome Laboratory, Flanders Interuniversity institute for Biotechnology (VIB4), Dept. Human Genetics, University of Leuve, Belgium
  • Guy Froyen, Human Genome Laboratory, Flanders Interuniversity institute for Biotechnology (VIB4), Dept. Human Genetics, University of Leuve, Belgium

    • Gene deletions or mutations are easily linked to human disease and therefore, the search for genetic mechanisms has up to now, mainly been focused to detect such aberrations. With the introduction of array-CGH and quantitative PCR-based methods, genome-wide detection of microdeletions and microduplications became possible. In our screening of a large cohort of patients with idiopathic X-linked mental retardation (XLMR) by full coverage X-chromosome-specific array-CGH we identified copy number alterations at a frequency of 10%. These aberrations vary in size from a few 100 kb up to several Mb. Besides deletions, often including parts of or entire known XLMR genes, several microduplications were detected. Duplications that segregate with the disease in the family and for which the female carriers show skewed X-inactivation are likely to contain a dosage-sensitive gene for which a 2-fold increase in mRNA expression results in disease. We recently identified small duplications (0.3 – 1.2 Mb) at Xq28 in 4 unrelated patients with severe MR, hypotonia and progressive spasticity. Double dosage of MECP2 was demonstrated as the underlying genetic cause. Additional screening by qPCR identified 10 more families with small Xq28 duplications including MECP2, which allowed for analysis of the recombination mechanism and for a detailed genotype-phenotype correlation study in these families. Similarly, we analyzed whether dosage-sensitive genes can explain the MR phenotypes in 13 other identified microduplications (0.2 – 10 Mb) on the X chromosome. Data on these will be discussed. Taken together, duplications resulting in increased gene dosage might represent a new common disease-associated mechanism for XLMR in particular or for disease in general.

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