Dosage-dependent severity of the phenotype in patients with mental retardation due to a recurrent copy-number gain at Xq28 mediated by an unusual recombination
| Autor: | E Pijkels, Peter Marynen, Hilde Van Esch, Karen Govaerts, Jürgen Kohlhase, Jelle Verbeeck, Christiane Spaich, Montserrat Milà, Isabel Fernandez, Jean-Pierre Fryns, Guido Froyen, Joke Vandewalle, Irene Madrigal, Anita Rauch, Christiane Zweier |
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| Přispěvatelé: | University of Zurich, Froyen, G |
| Rok vydání: | 2009 |
| Předmět: |
Adult
Male 2716 Genetics (clinical) Candidate gene Genetics and epigenetic pathways of disease [NCMLS 6] 10039 Institute of Medical Genetics MECP2 duplication syndrome Gene Dosage 610 Medicine & health Biology Gene dosage X-inactivation Article 03 medical and health sciences 0302 clinical medicine 1311 Genetics Intellectual Disability medicine Genetics Humans Genetics(clinical) Child Letter to the Editor Genetics (clinical) 030304 developmental biology Chromosome Aberrations Recombination Genetic Chromosomes Human X 0303 health sciences Models Genetic Breakpoint Brain Chromosome Mapping Nucleic Acid Hybridization Low copy repeats medicine.disease Phenotype Pedigree Xq28 Child Preschool 570 Life sciences biology Female Functional Neurogenomics [DCN 2] 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics, 85, 6, pp. 809-22 American Journal of Human Genetics, 85, 809-22 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2009.10.019 |
| Popis: | We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling Xq28-region-specific oligo array revealed that all aberrations start at the beginning of the low copy repeat LCR-K1, at position 153.20 Mb, and end just distal to LCR-L2, at 153.54 Mb. The copy-number gain always includes 18 annotated genes, of which RPL10, ATP6AP1 and GDI1 are highly expressed in brain. From these, GDI1 is the most likely candidate gene. Its copy number correlates with the severity of clinical features, because it is duplicated in one family with nonsyndromic moderate MR, is triplicated in males from two families with mild MR and additional features, and is present in five copies in a fourth family with a severe syndromic form of MR. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggests a recombination mechanism that involves two adjacent but different sets of low copy repeats. Taken together, our data strongly suggest that an increased expression of GDI1 results in impaired cognition in a dosage-dependent manner. Moreover, these data also imply that a copy-number gain of an individual gene present in the larger genomic aberration that leads to the severe MECP2 duplication syndrome can of itself result in a clinical phenotype as well. ispartof: American Journal of Human Genetics vol:85 issue:6 pages:809-22 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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