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
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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.
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Two unrelated males harbored Xq28 duplications, one de novo and one maternal, corresponding to a ∼0.3 Mb segmental-duplication-mediated gain (153.2-153.5 Mb), previously reported in X-linked ID.
“For example, two unrelated males were found to harbor Xq28 duplications (MIM 300815), one de novo and one maternal, corresponding to a ∼0.3 Mb segmental-duplication-mediated gain (153.2–153.5 Mb), which was previously reported in X-linked ID.42”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [42]
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- Authors
- Vandewalle, J., Van Esch, H., Govaerts, K., Verbeeck, J., Zweier, C., Madrigal, I., Mila, M., Pijkels, E., Fernandez, I., Kohlhase, J., Spaich, C., Rauch, A., Fryns, J.-P., Marynen, P., & Froyen, G.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Hospital Clínic de Barcelona (ES)
- Universitair Ziekenhuis Leuven (BE)
- Universidad de Valladolid (ES)
- University of Freiburg (DE)
- Olgahospital (DE)
- Corresponding author
- Froyen, Guy
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 85
- Issue
- 6
- Pages
- 809-822
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2790561
- OpenAlex
- W1990251817
- Cited by
- 86
- References
- 35
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 9 · 2013: 9 · 2012: 8
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- Instituto de Salud Carlos III
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- X-linked intellectual disability, GDI1, segmental duplication, recombination mechanisms, X chromosome inactivation, MECP2 duplication syndrome, ribosomal protein L10, ATP6AP1, gene dosage, mRNA expression
- MeSH terms
- Adult, Brain, Child, Child, Preschool, Chromosome Aberrations, Chromosome Mapping, Female, Humans, Male, Intellectual Disability, Models, Genetic, Nucleic Acid Hybridization, Pedigree, Phenotype, Recombination, Genetic, Gene Dosage, Chromosomes, Human, X
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