title: Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX 77030, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.forename: Ayelet
authors.initials: A
authors.lastname: Erez
authors.forename: Sandesh C Sreenath
authors.initials: SC
authors.lastname: Nagamani
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Simmons
authors.forename: Joanna
authors.initials: J
authors.lastname: Wiszniewska
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Eng
authors.forename: M Lance
authors.initials: ML
authors.lastname: Cooper
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Roeder
authors.forename: John B
authors.initials: JB
authors.lastname: Bodensteiner
authors.forename: Mauricio R
authors.initials: MR
authors.lastname: Delgado
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Prakash
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D023061:Gene Order; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D056916:Segmental Duplications, Genomic / Q000235:genetics; D016415:Sequence Alignment