Transcriptomics

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Mapping of the HUWE1 duplication at Xp11.22 in eight unrelated XLID patients


ABSTRACT: In a study to elucidate the genetic defects in patients with X-linked intellectual disability (XLID) we performed X chromosome-specific BAC-array-CGH and identified 0.33 to 1.0 Mb nonrecurrent copy number gains at Xp11.22 in affected males of unrelated XLID families. All aberrations segregate with the disease in the families and the carrier mothers show a nonrandom X-inactivation. Affected males suffered from mild to moderate ID. Tiling Xp11.22 region-specific oligo-array (ChrX:52.50 - 54.50 Mb) revealed that all aberrations had different start and stop sites. The twofold copy number gain included up to 20 genes but only the HUWE1 gene is located in the minimal common region of overlap in these families. Moreover, expression analysis revealed about twofold increased HUWE1 mRNA levels in affected patients when compared to control individuals. Breakpoint analysis revealed Non-homologous end-joining (4 cases), serial replication slippage (1 case) and non-allelic homologous recmbination (one case) as the potential recombination mechanism. For duplication mapping and exact copy number analysis in all four families, differentially-labeled patient versus male control DNA samples were hybridized onto a custom designed 4x44k oligo-array (Agilent Technologies) that covers the repeat-masked region 52.50 Mb to 54.50 Mb at tiling resolution.

ORGANISM(S): Homo sapiens  

SUBMITTER: Randi Hovland  Tulika Bose  Jelle Verbeeck  Stefanie Belet  Lucy Raymond  Siren Berland  Leslie Sheffield  Guy Froyen  Mark Corbett  Peter Marynen 

PROVIDER: E-GEOD-32945 | ArrayExpress | 2012-09-03

SECONDARY ACCESSION(S): GSE32945PRJNA146459

REPOSITORIES: GEO, ArrayExpress

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We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, in  ...[more]

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