title: 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.
abstract: 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.
authors.affiliation: Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Vandewalle
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Karen
authors.initials: K
authors.lastname: Govaerts
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: Irene
authors.initials: I
authors.lastname: Madrigal
authors.forename: Montserrat
authors.initials: M
authors.lastname: Mila
authors.forename: Elly
authors.initials: E
authors.lastname: Pijkels
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernandez
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Christiane
authors.initials: C
authors.lastname: Spaich
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D010641:Phenotype; D011995:Recombination, Genetic