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Original article
Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions
  1. Ayman W El-Hattab1,
  2. Ping Fang2,
  3. Weihong Jin2,
  4. Jeffrey R Hughes2,
  5. James B Gibson3,
  6. Gayle S Patel3,
  7. Dorothy K Grange4,
  8. Linda P Manwaring4,
  9. Ankita Patel2,
  10. Pawel Stankiewicz2,
  11. Sau Wai Cheung2
  1. 1Division of Medical Genetics, Department of Child Health, University of Missouri Health Care, Columbia, Missouri, USA
  2. 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  3. 3Clinical Genetics, ‘Specially for Children, Austin, Texas, USA
  4. 4Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
  1. Correspondence to Dr Sau W Cheung, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS NAB 2015, Houston, TX, 77030, USA; scheung{at}


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.

  • Chromosome Xq28 duplications
  • chromosome Xq28 deletions
  • X linked intellectual disability (XLID)
  • factor VIII (F8) gene
  • array comparative genomic hybridisation (array CGH)
  • clinical genetics
  • metabolic disorders
  • cytogenetics
  • getting research into practice
  • cystic fibrosis
  • copy-number
  • diagnostics tests
  • genetic screening/counselling
  • genetics
  • molecular genetics
  • clinical genetics
  • metabolic disorders
  • cytogenetics
  • getting research into practice
  • copy-number
  • diagnostics tests
  • genetic screening/counselling, genetics

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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  • Correction notice This article has been corrected since it was published Online First. The authors' competing interests have been added.

  • Competing interests Dr Sau Wai Cheung is the director of the Cytogenetics Laboratory, Department of Molecular and Human genetics, Baylor College of Medicine. The cytogenetic and molecular laboratories at Baylor College of Medicine offer extensive genetic laboratory testing including use of array CGH for genomic copy number analysis and derive revenue from this activity.

  • Ethics approval Institutional Review Board of Baylor College of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.