Abstract for presentation at 11th International Congress of Human Genetics

Identifying recurrent submicroscopic copy number changes in mentally retarded patients by array CGH and MLPA; the example of 2q23.1->q23.2

  • Erik Sistermans, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • David Koolen, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • Rolph Pfundt, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • Nicole de Leeuw, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • Willy Nillesen, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • Han Brunner, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands
  • Joris Veltman, Radboud University Nijmegen Medical Center, The Netherlands
  • Bert de Vries, Radboud University Nijmegen Medical Centre, dept of Human Genetics, The Netherlands

    • To date, the majority of submicroscopic interstitial anomalies in non-syndromic mental retardation (MR) patients are unique cases, hampering the delineation of the associated phenotype. The use of tiling resolution array CGH in routine diagnostics will change this situation, as it will lead to the identification of new aberrations. Subsequent testing by Multiplex Ligation-dependent Probe Amplification (MLPA) on large numbers of MR patients will reveal if these new aberrations are recurrent. Following this protocol, we recently detected a 920 Kb sized microdeletion, and a 594 Kb microduplication at 2q23.1->q23.2, partially overlapping a submicroscopic deletion, previously reported by our group. Severe MR, postnatal growth retardation, microcephaly, coarse facies and epilepsy were noted in both microdeletion patients. The duplication was detected in a severely mentally retarded boy with marked hypotonia.
    The identification of recurrent copy-number changes at 2q23.1->q23.2 suggests that this region may be prone to recombination and contains candidate genes involved in MR. The 317 Kb critical region at 2q23.1->q23.2 included two known genes: methyl-CpG binding domain protein 5 (MBD5), and enhancer of polycomb homolog 2 (EPC2). MBD5 is an autosomal homologue of MeCP2, implicated in Rett syndrome. Remarkably, some clinical overlap with Rett syndrome could be noted in our patients. In addition, duplication of MeCP2 causes severe MR and progressive neurological symptoms, as was also observed in our patient with a gain of 2q23.1->q23.2. Therefore, we performed mutation analysis of the candidate genes among 47 patients referred to our centre for MeCP2 analysis. Screening of the same patients and an additional cohort of 200 MR patients for copy number changes in the 2q23 region, using synthetic MLPA probes did not reveal any additional aberrations so far. Still, the overlap in clinical features between the two microdeletion patients points to a new MR syndrome.

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