P845 Compound heterozygous mutations in IL10RA combined with a hemizygous CFP mutation acting as a potential modifier in infantile-onset inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBDs) result from a complex interaction of host genetic factors, gut microbiome, and environmental stimuli.1 Although many genome-wide association studies have identified host genetic factors associated with IBD, rare Mendelian forms of IBD have been reported in patients with very early onset forms.2,3 Therefore, this study aimed to identify genetic variants associated with infantile-onset IBD. Genomic DNAs were obtained from whole blood of a male patient with infantile-onset IBD and non-consanguineous Korean parents. Pedigree of the patient. The patient’s older brother died due to complications of severe colitis. His brother also had multiple oral ulcers. The patient’s cousin had adolescent onset ulcerative colitis (UC). The sequenced trio are marked in blue. We performed whole-exome sequencing using trio samples. Then, we analysed the data using susceptibility genes for monogenic forms of IBD4,5,6 and various immunodeficiencies.7–10 Variants filtered for rare (minor allele frequency < 5% in the 1000 Genomes Project data) and nonsynonymous variants. The patient who presented with oral aphthous ulcers at the age of 14 days suffered from severe colitis and was refractory to medical treatment. Colonoscopy images from the patient. (A) A large ulceration (arrow) was noted in the sigmoid colon. (B) Colonic mucosa was friable and easy touch bled. After filtering out among more than 51000 genetic variants, compound-heterozygous mutations in IL10RA (p.R101W; p.T179T) were found in the patient. In addition, a hemizygous mutation in Complement Factor Properdin (CFP) (p.L456V) located on the X-chromosome was detected, inherited from the patient’s mother. het: heterozygous, hemi: hemizygous; dann: functional prediction score generated by deep learning; dbscSNV: for splice site prediction by AdaBoost and Random Forest het: heterozygous, hemi: hemizygous; dann: functional prediction score generated by deep learning; dbscSNV: for splice site prediction by AdaBoost and Random Forest The variant in CFP is predicted as “pathogenic” with a DANN score of 1, the highest possible score. Therefore, CFP mutation may also contribute to the phenotype of the patient as a genetic modifier. This study identified compound-heterozygous mutations in IL10RA combined with a hemizygous mutation in CFP acting as a potential modifier using whole-exome sequencing. 1. Ellinghaus D, Zhang H, Zeissig S, et al. Association between variants of PRDM1 and NDP52 and Crohn’s disease, based on exome sequencing and functional studies. Gastroenterology, 2013;2:339–47. 2. Glocker E-O, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med, 2009;21:2033–45. 3. Zeissig Y, Petersen B-S, Milutinovic S, et al. XIAP variants in male Crohn’s disease. Gut, 2015;1:66–76. 4. Al-Herz W, Bousfiha A, Casanova J-L, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol, 2011;2:54. 5. Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency 2015. J Clin Immunol, 2015. 6. Notarangelo LD, Fischer A, Geha RS, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol, 2009;6:1161–78. 7. Uhlig HH, Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut, 2013;12:1795–805. 8. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease,. Gastroenterology, 2014;5:990–1007. 9. Bianco AM, Girardelli M, Tommasini A. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World J Gastroenterol, 2015;43:12296–310. 10. Uhlig HH, Schwerd T, From genes to mechanisms: the expanding spectrum of monogenic disorders associated with inflammatory bowel disease. Inflamm Bowel Dis, 2016;1:202–12.