Personalised therapies in IBD: utilising next-generation sequencing data to direct treatment in monogenic disorders

Dror Shouval, P-ECCO Member

Dror Shouval

Over the past two decades, significant progress has been made in the understanding of the role of genetics in the pathogenesis of Inflammatory Bowel Disease (IBD): On the one hand, adult IBD studies have identified more than 250 single nucleotide polymorphisms that increase the risk of disease, though their individual and overall effect on the risk of developing IBD is small [1]. On the other hand, the expanding use of next-generation sequencing (NGS) platforms has resulted in the identification of more than 100 different rare monogenic disorders that directly cause IBD [2]. Given the central role of immune cells in sustaining immune tolerance in the gut, it is not surprising that in many cases monogenic disorders causing IBD result from pathogenic variants in genes involved in essential immune or epithelial pathways. Some patients with such disorders present with a clear immunodeficiency phenotype (e.g. chronic granulomatous disease, Wiskott-Aldrich syndrome), but in others IBD is the sole manifestation [3].

A variety of demographic, clinical and histological features should prompt work-up for a monogenic disorder [4], such as consanguinity, presentation at a young age (especially <2 years), recurrent severe or atypical infections, accompanying autoimmune features, and diffuse apoptosis or loss of germinal centres in intestinal histologic assessment. In a large cohort of 1005 IBD patients diagnosed at age <18 years, a monogenic disorder was identified in 31 cases, with a median age of 10.65 years at symptom onset [5]. Importantly, in 17/31 patients, diagnosis was established at age >10 years [5]. Moreover, other studies have reported identification of monogenic disorders in adolescent and adult patients resulting from deleterious mutations in XIAP [6], LRBA [7], CTLA4 [8], G6PC3 [9] and other genes. It is also important to consider a monogenic disorder in patients who are refractory to multiple lines of therapy. As an example, Holm Uhlig’s group identified a mutation in XIAP in an adult patient with a history of severe Crohn’s Disease since adolescence that required multiple surgeries, leading to short bowel syndrome and consideration for an intestinal transplantation [6].

In conclusion, extensive use of NGS in very young patients with unique IBD phenotypes has enabled the discovery of more than 100 different monogenic disorders, and in some cases facilitated administration of a targeted therapy. However, mounting evidence suggests that monogenic disorders causing IBD can present later in life, and a high index of suspicion is needed in patients with extreme phenotypes. With the reducing costs of NGS and the understanding of how results can impact clinical care and direct personalised therapies, efforts should be made to make these studies more accessible in unique cases and to integrate them into clinical practice.


  1. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–24. doi:10.1038/nature11582.
  2. Bolton C, Smillie CS, Pandey S, et al. An integrated taxonomy for monogenic inflammatory bowel disease. Gastroenterology. 2022;162:859–76. doi:10.1053/j.gastro.2021.11.014.
  3. Nambu R, Warner N, Mulder DJ, et al. A systematic review of monogenic inflammatory bowel disease. Clin Gastroenterol Hepatol. 2022;20:e653–63. doi:10.1016/j.cgh.2021.03.021.
  4. de Mesquita MB, Shouval DS. Evaluation of very early-onset inflammatory bowel disease. Curr Opin Gastroenterol. 2020;36:464–9. doi:10.1097/MOG.0000000000000680.
  5. Crowley E, Warner N, Pan J, et al. 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. 2020;158:2208–20. doi:10.1053/j.gastro.2020.02.023.
  6. Quaranta M, Wilson R, Gonçalves Serra E, et al. Consequences of identifying XIAP deficiency in an adult patient with inflammatory bowel disease. Gastroenterology. 2018;155:231–4. doi:10.1053/j.gastro.2018.03.069.
  7. Vardi I, Chermesh I, Werner L, et al. Monogenic inflammatory bowel disease: It's never too late to make a diagnosis. Front Immunol. 2020;11:1775. doi:10.3389/fimmu.2020.01775.
  8. Schwab C, Gabrysch A, Olbrich P, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142:1932–46. doi:10.1016/j.jaci.2018.02.055.
  9. Bolton C, Burch N, Morgan J, et al. Remission of inflammatory bowel disease in glucose-6-phosphatase 3 deficiency by allogeneic haematopoietic stem cell transplantation. J Crohns Colitis. 2020;14:142–7. doi:10.1093/ecco-jcc/jjz112.
  10. Shouval DS, Biswas A, Kang YH, et al. Interleukin 1beta mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology. 2016;151:1100-104. doi:10.1053/j.gastro.2016.08.055.
  11. Bader-Meunier B, Martins AL, Charnit-Henrion F, et al. Mevalonate kinase deficiency: a cause of severe very-early-onset inflammatory bowel disease. Inflamm Bowel Dis. 2021;27:1853–7. doi:10.1093/ibd/izab139.
  12. Sandborn WJ, Colombel J-F, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology. 2012;143:62–9 e64. doi:10.1053/j.gastro.2012.04.010.
  13. Egg D, Rump IC, Mitsuiki N, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149:736–46. doi:10.1016/j.jaci.2021.04.039.
  14. Canna SW, Girard C, Malle L, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139:1698–1701. doi:10.1016/j.jaci.2016.10.022.
  15. Geerlinks AV, Dvorak AM, XIAP Deficiency Treatment Consortium. A case of XIAP deficiency successfully managed with tadekinig alfa (rhIL-18BP). J Clin Immunol. 2022;42: 901–3. doi:10.1007/s10875-022-01236-2.

Posted in ECCO News, Committee News, P-ECCO, Volume 17, Issue 3