Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions
Open accessAbstract
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.
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Duplications of distal Xq28 have been reported in association with developmental delay in both sexes.
“Duplications of distal Xq28 have been reported in association with developmental delay in both sexes 23, 24.”
From Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects (2017) · cites this paper as [23]
Of 26 subjects described clinically, nearly half (12/26) have behavioral or psychiatric conditions.
“Notably, of 26 subjects that have been described clinically, nearly half (12/26) have behavioral or psychiatric conditions.”
From Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects (2017) · cites this paper as [23]
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Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
Marshall, C. R., Howrigan, D. P., Merico, D., Thiruvahindrapuram, B., Wu, W., Greer, D. S., Antaki, D., Shetty, A., Holmans, P. A., Pinto, D., et al. (2017) · Nature Genetics · doi:10.1038/ng.3725 · Cited by 1,058 · see citing works
El-Hattab, A. W., Schaaf, C. P., Fang, P., Roeder, E., Kimonis, V. E., Church, J. A., Patel, A., & Cheung, S. W. (2015) · BMC Medical Genetics · doi:10.1186/s12881-015-0157-2 · Cited by 53 · see citing works
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- Authors
- El-Hattab, A. W., Fang, P., Jin, W., Hughes, J. R., Gibson, J. B., Patel, G. S., Grange, D. K., Manwaring, L. P., Patel, A., Stankiewicz, P., & Cheung, S. W.
- Affiliations
- Baylor College of Medicine (US)
- Washington University in St. Louis (US)
- Corresponding author
- Cheung, Sau Wai
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2011-10-08
- Volume
- 48
- Issue
- 12
- Pages
- 840-850
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2102033696
- Cited by
- 59
- References
- 56
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 4 · 2012: 4
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of Medical Genetics (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- X-linked intellectual disability, Xq28 duplication, non-allelic homologous recombination, X-inactivation skewing, copy number variation, miscarriage, hyperactivity, aggression, facial dysmorphism
- MeSH terms
- Adolescent, Adult, Child, Developmental Disabilities, Child, Preschool, Chromosome Deletion, Chromosome Mapping, Female, Hemophilia A, Humans, Male, Intellectual Disability, Pedigree, Phenotype, Sex Chromosome Aberrations, Genome, Human, In Situ Hybridization, Fluorescence, Computational Biology, Sex Chromosome Disorders, Chromosomes, Human, X, X Chromosome Inactivation, Comparative Genomic Hybridization, DNA Copy Number Variations, Segmental Duplications, Genomic, Chromosome Duplication, Homologous Recombination
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