Sa1702 - Novel Insights on Thiopurine Induced Leukopenia and Pancreatitis from Whole-Exome Sequencing (Wes) of 1,321 Inflammatory Bowel Diseases (IBD) Patients

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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759 – Significant Variants in Monogenic Inflammatory Bowel Disease Genes Identified by Whole Exome Sequencing of 400 Paediatric Patients

Gastroenterology ◽

10.1016/s0016-5085(19)37187-2 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-157-S-158

Author(s):

James J. Ashton ◽

Enrico Mossotto ◽

Imogen Stafford ◽

Tracy Coelho ◽

Nadeem A. Afzal ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bowel Disease ◽

Disease Genes ◽

Paediatric Patients ◽

Whole Exome ◽

Inflammatory Bowel

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Faculty Opinions recommendation of Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8295956.793478790 ◽

2013 ◽

Author(s):

John Barnard

Keyword(s):

Inflammatory Bowel Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Application ◽

Bowel Disease ◽

Definitive Diagnosis ◽

Whole Exome ◽

Inflammatory Bowel

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Whole-Exome Sequencing in 10 Unrelated Patients with Syndromic Hidradenitis Suppurativa: A Preliminary Step for a Genotype-Phenotype Correlation

Dermatology ◽

10.1159/000521263 ◽

2022 ◽

pp. 1-10

Author(s):

Angelo Valerio Marzano ◽

Giovanni Genovese ◽

Chiara Moltrasio ◽

Paola Maura Tricarico ◽

Rossella Gratton ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hidradenitis Suppurativa ◽

Joint Inflammation ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation ◽

Whole Exome ◽

Immune Mediated ◽

Number Of Patients ◽

Bowel Diseases

Background: The genetics of syndromic hidradenitis suppurativa (HS), an immune-mediated condition associated with systemic comorbidities such as inflammatory bowel diseases and arthritis, has not been completely elucidated. Objective: To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. Methods: Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. Results: Three clinical settings have been identified based on presence/absence of gut and joint inflammation. Four PASH patients who had also gut inflammation showed three different variants in NOD2 gene, two variants in OTULIN, and a variant in GJB2, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in NCSTN, one in WDR1 and PSTPIP1, and two variants in NLRC4, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. Limitations: Limited number of patients that can be counterbalanced by the rarity of syndromic HS. Conclusion: Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.

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