Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review
Open accessAbstract
BACKGROUND: Int22h1/int22h2-mediated Xq28 duplication syndrome is caused by ~0.5 Mb chromosomal duplications mediated by nonallelic homologous recombination between intron 22 homologous region 1 (int22h1) and 2 (int22h2), which, in addition to int22h3, are also responsible for inversions disrupting the F8 gene in hemophilia A. This syndrome has recently been described in 9 males with cognitive impairment, behavioral problems, and distinctive facial features; and 6 females with milder phenotypes. The reciprocal deletion was previously reported in a mother and daughter. It was suggested that this deletion may not have phenotypic effects in females because of skewed chromosome X inactivation, but may be embryonic lethal in males. METHODS: Array comparative genomic hybridization analyses were performed using oligonucleotide-based chromosomal microarray. Chromosome X inactivation studies were performed at the AR (androgen receptor) and FMR1 (fragile X mental retardation 1) loci. RESULTS: We present here 5 males and 6 females with int22h1/int22h2-mediated Xq28 duplication syndrome. The males manifested cognitive impairment, behavioral problems, and distinctive facial features. Two of the six females manifested mild cognitive impairment. This duplication was maternally inherited, and skewed chromosome X inactivation was observed in the majority of females carrying the duplication. We also report the reciprocal deletion in a mother and daughter with overweight, but normal cognition. In addition, we present the first case of a prenatally diagnosed de novo int22h1/int22h2-mediated deletion in a healthy female infant. We reviewed individuals previously reported with similar or overlapping rearrangements and evaluated the potential roles of genes in the rearrangement region. CONCLUSIONS: The similarity of clinical features among individuals with the int22h1/int22h2-mediated Xq28 duplication supports the notion that this duplication causes a recognizable syndrome that affects males with females exhibiting milder phenotypes. It is suggested that the observed cognitive impairment in this syndrome results from increased dosage of RAB39B gene located within the duplicated region. Increased dosage of CLIC2 may also contribute to the phenotype. The reciprocal deletion results in skewed chromosome X inactivation and no clinical phenotype in females. Review of overlapping deletions suggests that hemizygous loss of VBP1 may be the cause for the proposed male lethality associated with this deletion.
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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 [24]
Of five reciprocal deletions detected in this study, none were observed in males, consistent with hemizygous loss of distal Xq28 being associated with recessive embryonic lethality in males.
“Of the five reciprocal deletions that were detected in this study, none were observed in males, consistent with hemizygous loss of distal Xq28 being associated with recessive embryonic lethality in males 24.”
From Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects (2017) · cites this paper as [24]
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 [24]
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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
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Rare copy number variation in extremely impulsively violent males
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- Authors
- El-Hattab, A. W., Schaaf, C. P., Fang, P., Roeder, E., Kimonis, V. E., Church, J. A., Patel, A., & Cheung, S. W.
- Affiliations
- Baylor College of Medicine (US)
- University of California, Irvine Medical Center (US)
- University of Southern California (US)
- Corresponding author
- Cheung, Sau Wai
- Venue
- BMC Medical Genetics
- Published
- 2015-03-14
- Volume
- 16
- Issue
- 1
- Pages
- 12-12
- ISSN
- 1471-2350 (ISSN-L)
- PMC
- PMC4422130
- OpenAlex
- W2047813205
- Cited by
- 53
- References
- 29
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 5
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Medical Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001414)
- National Center for Advancing Translational Sciences
- 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
- non-allelic homologous recombination, X-inactivation skewing, hemophilia A, prenatal diagnosis, de novo deletion, cognitive impairment
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Female, Humans, Infant, Introns, Male, Middle Aged, Pedigree, Sex Chromosome Disorders, Chromosomes, Human, X, X Chromosome Inactivation, Young Adult, Chromosome Duplication
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