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2 results on '"inherited defects"'

1. Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease.

Author

Kelsen, Judith R., Dawany, Noor, Moran, Christopher J., Petersen, Britt-Sabina, Sarmady, Mahdi, Sasson, Ariella, Pauly-Hubbard, Helen, Martinez, Alejandro, Maurer, Kelly, Soong, Joanne, Rappaport, Eric, Franke, Andre, Keller, Andreas, Winter, Harland S., Mamula, Petar, Piccoli, David, Artis, David, Sonnenberg, Gregory F., Daly, Mark, and Sullivan, Kathleen E.

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. [ABSTRACT FROM AUTHOR]

Published
2015
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2. Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease

Author

Kathleen E. Sullivan, Christopher J. Moran, David A. Piccoli, David Artis, Andreas Keller, Helen Pauly-Hubbard, Mark J. Daly, Harland S. Winter, Alejuandro Martinez, Britt-Sabina Petersen, Petar Mamula, Joanne Soong, Gregory F. Sonnenberg, Kelly Maurer, Judith R. Kelsen, Eric F. Rappaport, Marcella Devoto, Robert N. Baldassano, Mahdi Sarmady, Noor Dawany, Andre Franke, and Ariella Sasson

Subjects
Adult, Male, Aging, Adolescent, Antigens, CD19, Interleukin-10 Receptor alpha Subunit, Single-nucleotide polymorphism, Genome-wide association study, Cell Cycle Proteins, Disease, Biology, Article, Gene Frequency, CVID, IBD, common variable immune deficiency, inherited defects, innate and adaptive immunity, Germany, medicine, Humans, Exome, Genetic Predisposition to Disease, Child, Exome sequencing, Genetic Association Studies, Genetics, Hepatology, Gastroenterology, Immunologic Deficiency Syndromes, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, Minor allele frequency, Child, Preschool, Immunology, Mutation, Primary immunodeficiency, Human genome, Female
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.

Published
2015

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