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Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

ABSTRACT: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10^-10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10^-10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

SUBMITTER: Serra EG

PROVIDER: S-EPMC7035382 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

Serra Eva Gonçalves EG Schwerd Tobias T Moutsianas Loukas L Cavounidis Athena A Fachal Laura L Pandey Sumeet S Kammermeier Jochen J Croft Nicholas M NM Posovszky Carsten C Rodrigues Astor A Russell Richard K RK Barakat Farah F Auth Marcus K H MKH Heuschkel Robert R Zilbauer Matthias M Fyderek Krzysztof K Braegger Christian C Travis Simon P SP Satsangi Jack J Parkes Miles M Thapar Nikhil N Ferry Helen H Matte Julie C JC Gilmour Kimberly C KC Wedrychowicz Andrzej A Sullivan Peter P Moore Carmel C Sambrook Jennifer J Ouwehand Willem W Roberts David D Danesh John J Baeumler Toni A TA Fulga Tudor A TA Carrami Eli M EM Ahmed Ahmed A Wilson Rachel R Barrett Jeffrey C JC Elkadri Abdul A Griffiths Anne M AM Snapper Scott B SB Shah Neil N Muise Aleixo M AM Wilson David C DC Uhlig Holm H HH Anderson Carl A CA

Nature communications 20200221 1

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with ...[more]

PMID: 32081864

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Project description:IntroductionTherapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1β monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease.MethodsThis is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events.ResultsNineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p<0.01) and length of stay (p<0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period.ConclusionCanakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD.

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Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

Publications

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

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