Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center

Crowley, Eileen; Warner, Neil; Pan, Jie; Khalouei, Sam; Elkadri, Abdul; Fiedler, Karoline; Foong, Justin; Turinsky, Andrei L.; Bronte-Tinkew, Dana M.; Zhang, Shiqi; Hu, Jamie; Tian, David H.; Li, Dalin; Horowitz, Julie; Siddiqui, Iram; Upton, Julia; Roifman, Chaim M.; Church, Peter; Wall, Donna A.; Ramani, Arun; Kotlarz, Daniel; Klein, Christoph; Uhlig, Holm H.; Snapper, Scott B.; Gonzaga‐Jauregui, Claudia; Paterson, Andrew D.; McGovern, Dermot P.; Brudno, Michael; Walters, Thomas D.; Griffiths, Anne M.; Muise, Aleixo M.

doi:10.1053/j.gastro.2020.02.023

Cited by 78 publications

(89 citation statements)

References 56 publications

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“…In the recent past, the combination of microarray technology and bioinformatics has facilitated the understanding of molecular mechanisms and reliable diagnostic and therapeutic targets for diseases. Through these techniques, many new genes involved in complex human diseases such as cancer and autoimmune complications have also been discovered [ 6 , 7 ]. Several studies have identified disease-related genes and functional pathways by analyzing the expression profile between SLE and healthy controls [ 8 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

Liu

Wang

et al. 2020

BioMed Research International

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Objective. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by overexpression of antibodies against autoantigen. Although previous bioinformatics analyses have identified several genetic factors underlying SLE, they did not discriminate between naive and individuals exposed to anti-SLE drugs. Here, we evaluated specific genes and pathways in active and recently diagnosed SLE population. Methods. GSE46907 matrix downloaded from Gene Expression Omnibus (GEO) was analyzed using R, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), and hub genes between naive SLE individuals and healthy controls. Results. A total of 134 DEGs were identified, in which 29 were downregulated, whereas 105 were upregulated in active and newly diagnosed SLE cases. GO term analysis revealed that transcriptional induction of the DEGs was particularly enhanced in response to secretion of interferon-γ and interferon-α and regulation of cytokine production innate immune responses among others. KEGG pathway analysis showed that the expression of DEGs was particularly enhanced in interferon signaling, IFN antiviral responses by activated genes, class I major histocompatibility complex (MHC-I) mediated antigen processing and presentation, and amyloid fiber formation. STAT1, IRF7, MX1, OASL, ISG15, IFIT3, IFIH1, IFIT1, OAS2, and GBP1 were the top 10 DEGs. Conclusions. Our findings suggest that interferon-related gene expression and pathways are common features for SLE pathogenesis, and IFN-γ and IFN-γ-inducible GBP1 gene in naive SLE were emphasized. Together, the identified genes and cellular pathways have expanded our understanding on the mechanism underlying development of SLE. They have also opened a new frontier on potential biomarkers for diagnosis, biotherapy, and prognosis for SLE.

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Section: Introductionmentioning

confidence: 99%

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

Liu

Wang

et al. 2020

BioMed Research International

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Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated that 3% of pediatric IBD patients have monogenic forms of IBD 12 . Like the case presented here, many of these patients present at a very early age with severe disease that is difficult to treat 12 . The young age of our patient, the severity of disease requiring biologic therapy, and the presence of apoptosis on biopsy made this patient a strong candidate for genetic analysis to determine a potential monogenic cause of disease.…”

Section: Discussionmentioning

confidence: 99%

“…The young age of our patient, the severity of disease requiring biologic therapy, and the presence of apoptosis on biopsy made this patient a strong candidate for genetic analysis to determine a potential monogenic cause of disease. We first screened for variants in genes known to be associated with VEOIBD, and as this patient was male we focused on X-linked genes associated with intestinal epithelial apoptosis including FOXP3 and XIAP, and also autosomal recessive genes including LRBA, ARPC1B, and TTC7A (see 12 , 45 for a complete list of genes associated with apoptosis). However, neither variants in these genes nor other genes associated with VEOIBD were identified.…”

Section: Discussionmentioning

confidence: 99%

“…Very Early Onset Inflammatory Bowel Disease (VEOIBD) may be associated with monogenic disorders 1 – 11 . Recent studies have demonstrated that approximately 3% of Pediatric IBD patients have a monogenic cause for their disease and younger age at diagnosis is a risk factor 12 .…”

Section: Introductionmentioning

confidence: 99%

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The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Dhingani

Guo

Pan

et al. 2020

Sci Rep

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Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

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Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon‐based short‐read sequencing strategies

Clinton

Crinnion

McKibbin

et al. 2023

Molec Gen & Gen Med

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Background:The widespread adoption of exome sequencing has greatly increased the rate of genetic diagnosis for inherited conditions. However, the detection and validation of large deletions remains challenging. While numerous bioinformatics approaches have been developed to detect deletions from wholeexome sequencing and targeted panels, further work is typically required to define the physical breakpoints or integration sites. Accurate characterisation requires either expensive follow -up whole -genome sequencing or the time -consuming, laborious process of PCR walking, both of which are challenging when dealing with the repeat sequences which frequently intersect deletion breakpoints. The aim of this study was to develop a cost-effective, long-range sequencing method to characterise deletions.Methods: Genomic DNA was amplified with primers spanning the deletion using long-range PCR and the products purified. Sequencing was performed on MinION flongle flowcells. The resulting fast5 files were basecalled using Guppy, trimmed using Porechop and aligned using Minimap2. Filtering was performed using NanoFilt. Nanopore sequencing results were verified by Sanger sequencing.Results: Four cases with deletions detected following comparative read-depth analysis of targeted short-read sequencing were analysed. Nanopore sequencing defined breakpoints at the molecular level in all cases including homozygous breakpoints in EYS, CNGA1 and CNGB1 and a heterozygous deletion in PRPF31.All breakpoints were verified by Sanger sequencing. Conclusions:In this study, a quick, accurate and cost -effective method is described to characterise deletions identified from exome, and similar data, using nanopore sequencing.

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Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center

Cited by 78 publications

References 56 publications

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

IFN-γ Mediates the Development of Systemic Lupus Erythematosus

The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon‐based short‐read sequencing strategies

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