title: Genome rearrangements detected by SNP microarrays in individuals with intellectual disability referred with possible Williams syndrome.
abstract: BACKGROUND
  Intellectual disability (ID) affects 2-3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for approximately 50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge. With the advent of microarray techniques, submicroscopic genome alterations not associated with known syndromes are emerging as a significant cause of ID and MCA.
  
  
  RESULTS
  High-density SNP microarrays were used to determine genome wide copy number in 42 individuals: 7 with confirmed alterations in the WS region but atypical clinical phenotypes, 31 with ID and/or MCA, and 4 controls. One individual from the first group had the most telomeric gene in the WS critical region deleted along with 2 Mb of flanking sequence. A second person had the classic WS deletion and a rearrangement on chromosome 5p within the Cri du Chat syndrome (OMIM:123450) region. Six individuals from the ID/MCA group had large rearrangements (3 deletions, 3 duplications), one of whom had a large inversion associated with a deletion that was not detected by the SNP arrays.
  
  
  CONCLUSIONS
  Combining SNP microarray analyses and qPCR allowed us to clone and sequence 21 deletion breakpoints in individuals with atypical deletions in the WS region and/or ID or MCA. Comparison of these breakpoints to databases of genomic variation revealed that 52% occurred in regions harboring structural variants in the general population. For two probands the genomic alterations were flanked by segmental duplications, which frequently mediate recurrent genome rearrangements; these may represent new genomic disorders. While SNP arrays and related technologies can identify potentially pathogenic deletions and duplications, obtaining sequence information from the breakpoints frequently provides additional information.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Pani
authors.forename: Holly H
authors.initials: HH
authors.lastname: Hobart
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Morris
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Mervis
authors.forename: Patricia
authors.initials: P
authors.lastname: Bray-Ward
authors.forename: Kendra W
authors.initials: KW
authors.lastname: Kimberley
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Rios
authors.forename: Robin C
authors.initials: RC
authors.lastname: Clark
authors.forename: Maricela D
authors.initials: MD
authors.lastname: Gulbronson
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Gowans
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gregg
mesh_terms: D001483:Base Sequence; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D056916:Segmental Duplications, Genomic; D018980:Williams Syndrome / Q000150:complications* / Q000235:genetics
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