Chromosomal numerical aberrations and rare copy number variation in patients with inflammatory Bowel disease
Open accessAbstract
BACKGROUND AND AIMS: Inflammatory bowel diseases [IBD] have a complex polygenic aetiology. Rare genetic variants can cause monogenic intestinal inflammation. The impact of chromosomal aberrations and large structural abnormalities on IBD susceptibility is not clear. We aimed to comprehensively characterise the phenotype and prevalence of patients with IBD who possess rare numerical and structural chromosomal abnormalities. METHODS: We performed a systematic literature search of databases PubMed and Embase; and analysed gnomAD, Clinvar, the 100 000 Genomes Project, and DECIPHER databases. Further, we analysed international paediatric IBD cohorts to investigate the role of IL2RA duplications in IBD susceptibility. RESULTS: A meta-analysis suggests that monosomy X [Turner syndrome] is associated with increased expressivity of IBD that exceeds the population baseline (1.86%, 95% confidence interval [CI] 1.48 to 2.34%) and causes a younger age of IBD onset. There is little evidence that Klinefelter syndrome, Trisomy 21, Trisomy 18, mosaic Trisomy 9 and 16, or partial trisomies contribute to IBD susceptibility. Copy number analysis studies suggest inconsistent results. Monoallelic loss of X-linked or haploinsufficient genes is associated with IBD by hemizygous or heterozygous deletions, respectively. However, haploinsufficient gene deletions are detected in healthy reference populations, suggesting that the expressivity of IBD might be overestimated. One duplication that has previously been identified as potentially contributing to IBD risk involves the IL2RA/IL15R loci. Here we provide additional evidence that a microduplication of this locus may predispose to very-early-onset IBD by identifying a second case in a distinct kindred. However, the penetrance of intestinal inflammation in this genetic aberration is low [<2.6%]. CONCLUSIONS: Turner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.
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A 2023 meta-analysis found an increased expressivity of IBD in TS of 1.86% (95% CI 1.48%-2.34%).
“A 2023 meta-analysis found an increased expressivity of IBD in TS of 1.86% (95% CI 1.48%-2.34%),728 congruent with the findings in a previous systematic review reporting a prevalence range between 0.67% and 4%.729”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [728]
Inflammatory bowel disease (IBD) is more common among individuals with TS than the general population.
“Inflammatory bowel disease (IBD) is more common among individuals with TS than the general population.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [728]
IBD in TS may present at a younger age (mean 17.8 ± 2.3 years, range 3-41 years).
“IBD in TS may also present at a younger age (mean 17.8 ± 2.3 years, range 3-41 years),728 be more severe,729 and/or have unique treatment complications,732 although there is likely reporting bias.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [728]
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Clinical practice guidelines for the care of girls and women with Turner syndrome.
Gravholt, C. H., Andersen, N. H., Christin-Maitre, S., Davis, S. M., Duijnhouwer, A., Gawlik, A., Maciel-Guerra, A. T., Gutmark-Little, I., Fleischer, K., Hong, D., et al. (2024) · European Journal of Endocrinology · doi:10.1093/ejendo/lvae050 · Cited by 224 · see citing works
- Authors
- Dirvanskyte, P., Gurram, B., Bolton, C., Warner, N., Jones, K. D. J., Griffin, H. R., Genomics England Research Consortium, Park, J. Y., Keller, K.-M., Gilmour, K. C., Hambleton, S., Muise, A. M., Wysocki, C., & Uhlig, H. H.
- Affiliations
- University of Oxford (GB)
- The University of Texas Southwestern Medical Center (US)
- Great Ormond Street Hospital (GB)
- Hospital for Sick Children (CA)
- Newcastle University (GB)
- Deutsche Klinik für Diagnostik (DE)
- National Health Service (GB)
- University of Toronto (CA)
- John Radcliffe Hospital (GB)
- Corresponding author
- Uhlig, Holm H
- ORCID
- Venue
- Journal of Crohn s and Colitis
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-07-30
- Volume
- 17
- Issue
- 1
- Pages
- 49-60
- ISSN
- 1873-9946 (ISSN-L)
- 1876-4479
- PMC
- PMC9880952
- OpenAlex
- W4288855514
- Cited by
- 6
- References
- 59
- Citations by year
- 2026: 4 · 2024: 2
- FWCI
- 0.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Crohn s and Colitis (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Institute for Health Research
- Oxford Biomedical Research Centre
- Leona M. and Harry B. Helmsley Charitable Trust
- UK Medical Research Council (MR/R008019/1)
- Canadian Institutes of Health Research
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health (RC2DK118640, RC2DK122532)
- National Health Service England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- inflammatory bowel disease
- MeSH terms
- Chromosome Aberrations, Humans, Inflammation, Turner Syndrome, Inflammatory Bowel Diseases, DNA Copy Number Variations
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