Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center.,Gastroenterology

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Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center.
Gastroenterology ( IF 29.4 ) Pub Date : 2020-02-19 , DOI: 10.1053/j.gastro.2020.02.023
Eileen Crowley ₁ , Neil Warner ₂ , Jie Pan ₂ , Sam Khalouei ₃ , Abdul Elkadri ₄ , Karoline Fiedler ₂ , Justin Foong ₃ , Andrei L Turinsky ₃ , Dana Bronte-Tinkew ₂ , Shiqi Zhang ₂ , Jamie Hu ₂ , David Tian ₂ , Dalin Li ₅ , Julie Horowitz ₆ , Iram Siddiqui ₇ , Julia Upton ₈ , Chaim M Roifman ₈ , Peter C Church ₂ , Donna A Wall ₉ , Arun K Ramani ₃ , Daniel Kotlarz ₁₀ , Christoph Klein ₁₀ , Holm Uhlig ₁₁ , Scott B Snapper ₁₂ , Claudia Gonzaga-Jauregui ₆ , Andrew D Paterson ₁₃ , Dermot P B McGovern ₅ , Michael Brudno ₁₄ , Thomas D Walters ₂ , Anne M Griffiths ₂ , Aleixo M Muise ₁₅

Affiliation

SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada; School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland; Division of Pediatric Gastroenterology, Western University, Children's Hospital, London Health Sciences Centre, London, Ontario, Canada.
SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin.
F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, California.
Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, New York.
Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
Blood and Marrow Transplant/Cellular Therapy, Haematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
Dr von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
Translational Gastroenterology Unit, University of Oxford, UK; Department of Pediatrics, University of Oxford, UK.
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts.
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background & Aims

A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

Methods

We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0–18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses.

Results

We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6–18 years. Of the 17 patients with monogenic Crohn’s disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation.

Conclusions

In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.

中文翻译：

通过单中心的1000名儿童的全外显子组测序确定与单基因变异相关的炎性肠病的患病率和临床特征。

背景与目标

一部分患有炎症性肠病（IBD）的婴幼儿具有与单个基因变异相关的亚型（单基因IBD）。我们的目的是确定一群IBD患儿的单基因疾病的患病率。

方法

我们在加拿大的一个中心及其家庭成员中对1005名年龄在0-18岁（诊断中位年龄为11.96岁）的1005名IBD儿童进行了全样本基因组测序分析。使用Sanger测序验证了导致IBD的变异体。通过免疫荧光和组织化学分析对患者的活检进行分析。

结果

我们在1005名IBD儿童中鉴定了40个与21个单基因基因相关的罕见变体（包括XIAP中的5个变体，DOCK8中的3个变体以及FOXP3，GUCY2C和LRBA中的每个2个））。这些变异发生在7.8％的6岁以下儿童和2.3％的6-18岁儿童中。在17例克罗恩病单基因病患者中，有35％的人出现腹痛，有24％的人无血便便，有18％的人呕吐，有18％的人体重减轻，有5％的人有间歇性的血性便便。14例单基因溃疡性结肠炎或IBD未分类的患者在年轻时接受了诊断，其主要特征是便血便便（78％）。与没有单一变异的IBD病例相比，与单基因IBD有关的特征是发病年龄小于2岁（优势比[OR]，6.30；P = .020），自身免疫性疾病的家族史（OR，5.12）；P = .002），肠外表现（OR，15.36；P<.0001）和手术（OR，3.42; P = .042）。17名患者的基因变异可以用同种异体造血干细胞移植纠正。