Judith R Kelsen1, Noor Dawany2, Christopher J Moran3, Britt-Sabina Petersen4, Mahdi Sarmady2, Ariella Sasson2, Helen Pauly-Hubbard5, Alejandro Martinez5, Kelly Maurer6, Joanne Soong7, Eric Rappaport8, Andre Franke4, Andreas Keller9, Harland S Winter3, Petar Mamula5, David Piccoli5, David Artis7, Gregory F Sonnenberg7, Mark Daly10, Kathleen E Sullivan6, Robert N Baldassano5, Marcella Devoto11. 1. Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia. Electronic address: Kelsen@email.chop.edu. 2. Department of Biomedical Health Informatics, The Children's Hospital of Philadelphia. 3. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Massachusetts General Hospital for Children. 4. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Germany. 5. Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia. 6. Division of Immunology and Allergy, The Children's Hospital of Philadelphia. 7. Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Department of Microbiology and Immunology, and The Jill Robert's Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, New York, New York. 8. Nucleic Acid/Polymerase Chain Reaction Core, The Children's Hospital of Philadelphia. 9. Department of Clinical Bioinformatics, Saarland University, Germany. 10. Analytic and Translational Unit Center for Human Genetic Research Department of Medicine, Massachusetts General Hospital; The Broad Institute of MIT and Harvard. 11. Division of Human Genetics, The Children's Hospital of Philadelphia; Department of Pediatrics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania; Department of Molecular Medicine, University Sapienza, Rome, Italy.
Abstract
BACKGROUND & AIMS: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. METHODS: Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn's disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. RESULTS: Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. CONCLUSIONS: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.
BACKGROUND & AIMS: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. METHODS:Patients with VEO-IBD and parents (when available) were recruited from the Children's Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn's disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. RESULTS: Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19. CONCLUSIONS: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.
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