Chromosomal Numerical Aberrations and Rare Copy Number Variation in Patients with Inflammatory Bowel Disease

Author:

Dirvanskyte Paulina1,Gurram Bhaskar2,Bolton Chrissy34ORCID,Warner Neil5,Jones Kelsey D J46,Griffin Helen R7,Park Jason Y8ORCID,Keller Klaus-Michael9,Gilmour Kimberly C10,Hambleton Sophie7,Muise Aleixo M511121314ORCID,Wysocki Christian15,Uhlig Holm H11617,

Affiliation:

1. Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, University of Oxford , Oxford , UK

2. Department of Pediatrics, UT Southwestern Medical Center , Dallas TX , USA

3. Institute of Child Health, University College London , London , UK

4. Paediatric Gastroenterology Department, Great Ormond Street Hospital for Children NHS Foundation Trust , London , UK

5. SickKids Inflammatory Bowel Disease Centre, Hospital for Sick Children , Toronto, ON , Canada

6. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford , Oxford , UK

7. Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute , Newcastle upon Tyne , UK

8. Department of Pathology and the Eugene McDermott Center for Human Growth and Development. UT Southwestern Medical Center , Dallas, TX , USA

9. German Clinic for Diagnostics [DKD], Helios Klinik , Wiesbaden , Germany

10. Laboratory of Immunology and Cellular Therapy, Great Ormond Street Hospital for Children, NHS Foundation Trust , London , UK

11. Department of Biochemistry, University of Toronto , Toronto, ON , Canada

12. Cell Biology Program, Sick Kids Research Institute, Hospital for Sick Children , Toronto, ON , Canada

13. Department of Pediatrics, University of Toronto , Toronto, ON , Canada

14. Institute of Medical Science, University of Toronto , Toronto, ON , Canada

15. Department of Pediatrics, and Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX , USA

16. Biomedical Research Centre, University of Oxford , Oxford , UK

17. Department of Paediatrics, John Radcliffe Hospital , Oxford , UK

Abstract

AbstractBackground and AimsInflammatory 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.MethodsWe 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.ResultsA 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%].ConclusionsTurner syndrome is associated with increased susceptibility to intestinal inflammation. Duplication of the IL2RA/IL15R loci may contribute to disease risk.

Funder

National Institute for Health Research

Oxford Biomedical Research Centre

Leona M. and Harry B. Helmsley Charitable Trust

UK Medical Research Council

Canadian Institutes of Health Research

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

National Health Service England

Wellcome Trust

Cancer Research UK

Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,General Medicine

Reference58 articles.

1. Translating immunology into therapeutic concepts for inflammatory bowel disease.;Uhlig;Ann Rev Immunol,2018

2. Pathway paradigms revealed from the genetics of inflammatory bowel disease.;Graham;Nature,2020

3. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.;de Lange;Nat Genet,2017

4. Sequencing of over 100 000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility;Sazanovs;medRxiv,2021

5. The diagnostic approach to monogenic very early onset inflammatory bowel disease.;Uhlig;Gastroenterology,2014

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