title: Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions.
abstract: BACKGROUND
  X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants.
  
  
  METHODS
  Array CGH analysis was performed using chromosomal microarray with ∼105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification.
  
  
  RESULTS
  A novel ∼0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions.
  
  
  CONCLUSIONS
  The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.
authors: Division of Medical Genetics, Department of Child Health, University of Missouri Health Care, Columbia, Missouri, USA.
authors: Ayman W
authors: AW
authors: El-Hattab
authors: Ping
authors: P
authors: Fang
authors: Weihong
authors: W
authors: Jin
authors: Jeffrey R
authors: JR
authors: Hughes
authors: James B
authors: JB
authors: Gibson
authors: Gayle S
authors: GS
authors: Patel
authors: Dorothy K
authors: DK
authors: Grange
authors: Linda P
authors: LP
authors: Manwaring
authors: Ankita
authors: A
authors: Patel
authors: Pawel
authors: P
authors: Stankiewicz
authors: Sau Wai
authors: SW
authors: Cheung
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D005260:Female; D015894:Genome, Human; D006467:Hemophilia A / Q000235:genetics / Q000473:pathology; D059765:Homologous Recombination; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D056916:Segmental Duplications, Genomic; D012729:Sex Chromosome Aberrations; D025064:Sex Chromosome Disorders / Q000235:genetics* / Q000473:pathology; D049951:X Chromosome Inactivation