title: A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.
abstract: BACKGROUND
  Children 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.
  
  
  METHODS
  We 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Kelsen@email.chop.edu.|7NW, Division of Pediatric Gastroenterology, 3400 Civic Center Blvd, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. Kelsen@email.chop.edu.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kelsen
authors.affiliation: Department of Biomedical Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Dawanyn@email.chop.edu.
authors.forename: Noor
authors.initials: N
authors.lastname: Dawany
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. martinezad@email.chop.edu.
authors.forename: Alejuandro
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. grochowskic@email.chop.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grochowski
authors.affiliation: Division of Immunology and Allergy, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. dietzmann@email.chop.edu.
authors.forename: Kelly
authors.initials: K
authors.lastname: Maurer
authors.affiliation: Nucleic Acid/PCR Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Rappaport@email.chop.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Rappaport
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. piccoli@email.chop.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Piccoli
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Baldassano@email.chop.edu.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. mamula@email.chop.edu.
authors.forename: Petar
authors.initials: P
authors.lastname: Mamula
authors.affiliation: Division of Immunology and Allergy, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. sullivank@email.chop.edu.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.affiliation: 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. devoto@email.chop.edu.
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
mesh_terms: D017668:Age of Onset; D056915:DNA Copy Number Variations; D059472:Exome; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000150:complications / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008232:Lymphoproliferative Disorders / Q000150:complications / Q000235:genetics*; D008297:Male