A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

Judith R Kelsen,Kathleen E Sullivan,Noor Dawany,Robert N Baldassano,Eric Rappaport,David A Piccoli,Marcella Devoto,Petar Mamula,Kelly Maurer,Alejuandro Martinez,Christopher M Grochowski

doi:10.1186/s12876-015-0394-z

Abstract

BackgroundChildren with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD.Case PresentationWe report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP.ConclusionThis is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies.

Highlights

Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population
X-linked lymphoproliferative Disease 2 (XLP2) is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH
Primary immunodeficiencies are a heterogeneous group of disorders that range in severity and clinical presentation, and may lead to immune dysregulation such as severe inflammatory bowel disease (IBD), most frequently in patients with very early-onset IBD (VEO-IBD)

Summary

Conclusion

Due to the extensive differential in the work up of our patient with severe VEO-IBD, generation sequencing technology can be of benefit. To evaluate for identified monogenic defects in VEO-IBD, or WES to study the whole exome, can offer a quicker method of analysis rather than a gene-by-gene approach. The results of this critical finding directed the course of action of treatment. Study concept and design: Kelsen, Dawany, Piccoli, Mamula, Baldassano, Sullivan, Devoto. Analysis and interpretation of data: Kelsen, Dawany, Rappaport, Sullivan, Baldassano, Devoto, Maurer, Grochowski. Drafting of the manuscript: Kelsen, Dawany, Baldassano, Mamula, Sullivan, Devoto. Critical Revision of Analysis of the manuscript for important intellectual content: Kelsen, Dawany, Piccoli, Mamula, Sullivan, Baldassano, Devoto.

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