Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications

Pengfei Liu, Ayelet Erez, Sandesh C Sreenath Nagamani, Weimin Bi, Claudia M B Carvalho, Alexandra D. Simmons, Joanna Wiszniewska, Ping Fang, Patricia A. Eng, M. Lance Cooper, V. Reid Sutton, Elizabeth R. Roeder, John B. Bodensteiner, Mauricio R. Delgado, Siddharth K. Prakash, John W. Belmont, Pawel Stankiewicz, Jonathan S. Berg, Marwan Shinawi, Ankita PatelSau Wai Cheung, James R. Lupski

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51 Scopus citations

Abstract

Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.

Original languageEnglish (US)
Article numberddr078
Pages (from-to)1975-1988
Number of pages14
JournalHuman Molecular Genetics
Volume20
Issue number10
DOIs
Publication statusPublished - May 2011

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Liu, P., Erez, A., Nagamani, S. C. S., Bi, W., Carvalho, C. M. B., Simmons, A. D., ... Lupski, J. R. (2011). Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications. Human Molecular Genetics, 20(10), 1975-1988. [ddr078]. https://doi.org/10.1093/hmg/ddr078