Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements

Guy Froyen*, Stefanie Belet, Francisco Martinez, Cintia Barros Santos-Reboucas, Matthias Declercq, Jelle Verbeeck, Lene Donckers, Siren Berland, Sonia Mayo, Monica Rosello, Marcia Mattos Goncalves Pimentel, Natalia Fintelman-Rodrigues, Randi Hovland, Suely Rodrigues dos Santos, F. Lucy Raymond, Tulika Bose, Mark A. Corbett, Leslie Sheffield, Conny M. A. van Ravenswaaij-Arts, Trijnie DijkhuizenCharles Coutton, Veronique Satre, Victoria Siu, Peter Marynen

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    56 Citations (Scopus)

    Abstract

    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, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.

    Original languageEnglish
    Pages (from-to)252-264
    Number of pages13
    JournalAmerican Journal of Human Genetics
    Volume91
    Issue number2
    DOIs
    Publication statusPublished - 10-Aug-2012

    Keywords

    • UBIQUITIN LIGASE HUWE1
    • LINKED MENTAL-RETARDATION
    • INTELLECTUAL DISABILITY
    • HUMAN GENOME
    • CHROMOSOMAL REARRANGEMENTS
    • MAMMALIAN-CELLS
    • MECP2 GENE
    • DUPLICATION
    • ARCHITECTURE
    • DISEASE

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