FMR1 gene expansion, large deletion of Xp, and skewed X-inactivation in a girl with mental retardation and autism

Authors

  • Alzbeta Vazna,

    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Zuzana Musova,

    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Marketa Vlckova,

    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Dhahuse Novotna,

    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Lenka Dvorakova,

    1. Institute of Inherited Metabolic Disorders, Charles University, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic
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  • Michal Hrdlicka,

    1. Department of Child Psychiatry, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Marketa Havlovicova,

    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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  • Zdenek Sedlacek

    Corresponding author
    1. Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
    • Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, V Uvalu 84, 15006 Prague 5, Czech Republic.
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  • How to Cite this Article: Vazna A, Musova Z, Vlckova M, Novotna D, Dvorakova L, Hrdlicka M, Havlovicova M, Sedlacek Z. 2010. FMR1 gene expansion, large deletion of Xp, and skewed X-inactivation in a girl with mental retardation and autism. Am J Med Genet Part A 152A:1273–1277.

Abstract

We describe a girl with mild facial anomalies, mild mental retardation, and atypical autism with a remarkable behavioral phenotype of persistent anger, aggression, and dysphoria. The occurrence of late-onset tremor and premature ovarian failure in the maternal branch of the family pointed to a possible defect in the FMR1 gene. Indeed, the patient carried a full FMR1 mutation. Unexpectedly, both alleles of the gene were almost completely methylated. Cytogenetic examination of the patient revealed in addition a large de novo deletion in band Xp22 on one of her X chromosomes. The deletion was fine mapped using oligonucleotide array CGH, and its breakpoints were localized using sequencing. The size of the deletion was about 17.4 Mb, and it contained more than 90 protein-coding genes. Microsatellite analysis indicated paternal origin of the aberrant chromosome. The large rearrangement was the most probable cause of the X-inactivation skewing, thus explaining the methylation of not only the expanded (maternal) but also the normal (paternal) FMR1 alleles. This pattern of skewed X-inactivation was confirmed using the analysis of methylation at the AR locus. The relatively mild phenotype of the patient resulted most likely from unmasking of the FMR1 defect. Although the deleted region contained many important genes, the phenotypic contribution of the rearranged X chromosome was probably limited by its almost complete inactivation. However, reduced dose of several genes escaping X-inactivation might also play a role in the phenotype of the patient. © 2010 Wiley-Liss, Inc.

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