Genetic Predispositions and Causative Factors to Early Onset IBD

Overview

Recent epidemiologic research shows an increasing incidence of VEO-IBD, largest in younger diagnoses. By identifying these genetic mutations, treatment can be appropriately tailored towards each specific case of VEO-IBD and allow for more successful remission.

School

School of Nursing

Programs

Researcher

Emily Whitters '26

Nursing

School of Nursing

What are the genetic predispositions and causative factors to early onset IBD in individuals under 18 years of age?

Background

VEO-IBD, or Very Early Onset Inflammatory Bowel Disease, is defined by the development of chronic inflammation of the intestinal tract prior to 6 years of age. IBD is classified into 3 categories, Crohn's Disease, Ulcerative Colitis, and IBD unclassified. VEO-IBD patients typically experience more severe disease course and high rates of unresponsiveness to treatment. Recent epidemiologic research shows an increasing incidence of VEO-IBD, largest in younger diagnoses. By identifying these genetic mutations, treatment can be appropriately tailored towards each specific case of VEO-IBD and allow for more successful remission.

Methods

A systematized review of databases CINAHL and PubMED was conducted with the following search string:

"Genetic Predisposition to Disease"[tw] AND ("Inflammatory Bowel Diseases/genetics"[MeSH] OR "Crohn Disease/genetics"[MeSH]) AND ("age of onset"[tw] OR veo OR "very early onset")

Following initial search, a total of 176 articles were retrieved. Articles were screened via title, abstract and full text with the following criteria:

Inclusion Criteria:

Evaluates genetic mutations as an epidemiological identifier
Age 18 or younger
Published within 5 years of search

Exclusion Criteria:

Not IBD specifically
Not early or very early onset IBD
Not published in English

Articles meeting all requirements after full text review (n=10) and hand/history searching (n=1) were appraised using the Critical Appraisal Skills Programme (CASP) checklists for the appropriate methodology (2026). Articles were scored:

“High” if there were less than 3 items on the checklist that did not meet “yes” Criteria.
“Moderate” if there were 3-5 items not meeting “yes”
“Low” if greater than 5 items not meeting “yes”

See the Table of Evidence for more details. Articles scoring “low” on the CASP checklist were excluded from this review (n=0).

Table of Evidence

Citation (APA format)	Study Design	Purpose	Population, Sample Size, and Setting	Genes Studied	Study Conclusion & Implications for Practice	Study Limitations	Level of Evidence & Evidence Quality (CASP Score)
Watson, A., et. al (2025)	Retrospective Cohort Study	Identify polygenic origins of VEO-IBD in a cohort with high proportion of Hispanic Patients.	Population: inclusion criteria included confirmed diagnosis of IBD, 6 years of age or younger at first presentation, underwent WES, and followed at TCH for at least 1 year. Sample size: 56 patients. Setting 54 patients went through WES at Baylor Genetics and 2 underwent WES through the Department of Pediatric Allergy and Immunology at BCM/TCH. 53.6% were male, 32.1% Hispanic, 26.8% White, 14.3% Asian, 10.7% Black.	MYO5B, DOCK8, LRBA, TRIM22, NCF1	MYO5B was identified as a key participant in the polygenic landscape of VEO-IBD. The results of these histological observations identify possible gene expressions that can help future diagnostic, predictive, and therapeutic discovery.	Small sample size (56 patients). Validation of the genetic predictors of presentation and outcome validation is required in larger cohorts.	Level IV, High Quality
Usman, Y., et al (2025)	Case Report	Case report of a Hispanic male with VEO-IBD due to a novel IL10RB variant.	Population: Male infant of Hispanic Descent with VEO-IBD confirmed at 9.5 months of age. Sample Size: 1 patient. The sudy was conducted through the Children's Hospital of Chicago.	IL10RB, STAT3, JAK1/2	This study exapnds on IL10RB variant for VEO-IBD and contributes to understanding genotype/phenotype correlations. The patient in this case shows a correlation between development of VEO-IBD due to a novel IL10RB variant whos disease course illustrated characteristic phenotype and challenges in management of IL-10R deficiency associated IBD. This case highlights that clinicians should consider a monogenic cause in infants with severe refractory IBD. Case experiences like this help improve future diagnosis and treatment of this rare disease.	Small sample of 1 patient case. The patient was of Hispanic decent, male, and born to parents who are first cousins.	Level VI, Moderate Quality
Wang, Q. et al, (2023)	Case Report	Case report of a 3 year old male of Chinese descent with VEO-IBD. By using a CBA assay to measure serum levels of proinflammatory cytokines in relation to the inflammatory response of the patient.	Population: 3 year old Chinese boy with confirmed VEO-IBD who carries the MEFV S242G variant. Sample size: 1 patient. Patients evaluated under protocol approved by the Institutional Review Board Children's Hospital of Zhejiang University School of Medicine.	MEFV, IL-1B, IL-10	Findings suggestedd that MEFV S242G mutation affected 14 3-3 protein binding and inhibitation, promoted pyrin inflammasome constitutive activation, and resulted in the ober profuction of proinflammatory cytokines IL-1B and IL-18 leading to the development of VEO-IBD in this patient. This proves the importance of inflammasomes in the development of IBD.	Small population size of 1 patient, of Chinese descent.	Level VI, Moderate Quality
Serra, E. G. et al (2020).	Retrospective Cohort Study	Whole exome sequencing and genome wide genotyping in 146 patients with VEO-IBD in whom no Mendelian disorders were clinically suspected.	Population: inclusion criteria included confirmed diagnosis of IBD by standard methods, and selected according to age of diagnosis (<7 years of age, with symptom onset, <6 years), as well as the severity of the IBD phenotype. If genetic diagnosis was established, the individual was excluded from the study. Sample size: the cohort consisted of 146 VEO-IBD cases without a previous genetic diagnosis and 4436 healthy controls. Setting: Participants were selected from facilities in the UK, Switzerland, Poland and Germany.	IL10, IL10RA, IL10RB	Primary immunodeficiencies caused by rare genetic variants can be found in some VEO-IBD patients even if no Mendelian diseasewas clinically suspected suggesting that genetic screening is relavent across the entire group of patients. Whatever factors are driving an early age of disease onset in individuals without a conclusive Mendelian diagnosis in the majority of patients, they do so on a polygenic background similar to classic IBD. This discovery indicates a polygenic component operates in VEO-IBD pathogenesis.	Sample patients were chosen based off a specific inclusion critera limiting the generalizability of the study, and creating bias.	Level IV, Moderate Quality
Abu Shtaya, A., et al (2025).	Retrospective Cohort Study	Estimate the carrier frequency of disease causing MEFV variants in pediatric patients with VEO-IBD in relation to the genetic similarities to familial Mediterranean Fever (FMF).	Population: Children highly suspected to have VEO-IBD with relatable IBD symptoms that started before 6 years of age. Diagosis based on combination of history, physical, and laboratory exams. Children who had undergone previous genetic testing that identified candiate genes for IBD were excluded. Sample size: 23 Patients under 6 years of age. Setting: Sequencing was performed at labs in Germany, California, Iowa, and Texas.	IL10RA/B, CYBB, LRBA	MEFV disease causing variants were detected in 52% of patients in the cohort, 3x the rate of the control group. The allelic frequency of the disease-causing variants were deteced in the IBD group irrespective of ethnicity. Clinical importance of these findings specifically towards future development of overt FMF symptoms is still unknown and more studies are needed to elucidate this point. Disease causing variants in the MEFV gene should be sought in cases of VEO-IBD.	Retrospective study, differences observed in association levels in the two groups may have been a consequence of the small sample size of 23 pateints.	Level IV, Moderate Quality
Watson, A., et al (2023).	Retrospective Cohort Study	Identify the presence of NOD2 polymorphisms in patients with VEO-IBD might confer a CD-Like phenotype, linear growth impairment, and arthropathy.	Population: patients diagnosed with VEO-IBD with symptoms presenting before age 6. Sample Size: 10 Patients with identified NOD2 polymorphisms, 2 on WES and the remaining on targeting sequencing panels. Comparison cohort comprised of 16 VEO-IBD patients with no genetic variants in VEO-IBD related genes on WES. Setting: All WES studies were performed at Baylor College of Medicine, Baylor Genetics in Houston Texas.	NOD2/CARD15	This discovery cohort demonstrates the important phenotypic differences potentially driven by NOD2 variants. NOD2 variants demonstrated a gene-dosage effect by homozygous or compound heterozygous polymorphisms associated with younger age at diagnosis and more severe disease. The small cohort of VEO-IBD patients did not find such associations from NOD2 variants as there was no signifigant difference in age at presentation or disease severity in the selected patients with compound heterozygous NOD2 polymorphisms verus those with just one NOD2 variant.	Small cohort size. These findings should be validated in larger cohorts to further delineate the effects of NOD2 polymorphisms on VEO-IBD and may guide precision medicine for patients with VEO-IBD in the future.	Level IV, Moderate Quality
Crowley, E., et al (2020).	Single Center Cohort Study	Utilizing WES to interrogate the currently known monogenic IBD genes to determine prevalence in pediatric patients with IBD and identify phenotypic characteristics indicative of monogenic disease.	Population: IBD patients and their families diagnosed and/or followed at SickKids under the age of 18. Sample Size: 1005 pediatric patients and their family members totaling to 2305 samples. Setting: All testing was performed at The Hospital for Sick Children in Toronto, Canada.	XIAP, DOCK8, FOXP3, GUCY2C, LRBA.	In whole exome sequencing analyses of over 1000 children with IBD at a single center, 3% had rare variants in genes previously associated with pediatric IBD. 40 rare variants were identified with 21 monogenic genes among 31 of the 1005 patients. This study likely underestimates the contribution of monogenic gene disorders in pediatric IBD. Although monogenic IBD is rare, it should be considered in the analysis of all patients with pediatric IBD.	Limitations involving the WES methodology, including approximately 5% of exons poorly covered. With a rapid increase in the discovery of monogenic IBD genes it is anticipated that more genes will continue to be discovered.	Level IV, Moderate Quality
Ashton, J. J., et al (2020).	Retrospective Cohort Study	Apply exome sequencing to a cohort of typical pediatric patients with IBD to identify clinically relevant variants within monogenic IBD genes.	Population: inclusion criteria included confirmed histological diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified, and are under the age of 18, mean age at diagnosis was 11.9 years. Sample size: 401 patients. Setting: Wessex regional pediatric IBD service at Southampton Childrens Hospital in England.	NOD2, TRIM22, DCLRE1C, LRBA.	11.5% of patients harbored a monogenic variant identified as either pathogenic or likely pathogenic. Findings are consistent with monogenic NOD2-related disease, which represents molecular basis of 5% of all pediatric IBD cases. Majority of cases contained compound heterozygous variants. Data implys distinct clinical characteristics that segregate with monogenic NOD2-related disease. NOD2 is the risk gene mostly associated with Crohn's disease. Making diagnoses using precise molecular data can lead to personalized therapyy in select patients.	This study was limited by identifying only commonly reported NOD2 variants, and did not account for additional rare or novel variants.	Level IV, High Quality
Parlato, M., et al (2020).	Clinical Study	Identifying PTPN2 haploinsufficiency as a monogenic cause of intestinal autoimmunity.	Population: patients were selected based on severe chronic diarrhea developed before 6 years of age and refractory to medical treatment. Sample size: 1 patient, 3 year old female. Control obtained from a 4 year old male with unconfirmed gastroenteritis. Setting: Paris, France.	PTPN2, JAK, STAT3.	Impaired negative regulation of JAK-STAT signaling was observed in the patients lymphocytes. Severe autoimmune enteropathy or enterocolitis is also a hallmark of STAT3 GOF mutations. This highlights the need of tightly regulating JAK-STAT activation to restrict intestinal inflammation.	This study involved a small sample of only 1 patient selected using specific criteria.	Level VI, Moderate Quality
Charbit-Henrion, F., et al (2018).	Retrospective Cohort Study	Define how next generation sequencing methods can be used to improve identification of known molecular diagnosis and to adapt treatment.	Population: inclusion criteria included chronic diarrhea devloped before 6 years of age, with severe disease course requiring immunosuppressive treatments, sugery, and/or parenteral nutrition. Sample size: 207 patients. Setting: ESPGHAN GENIUS working group.	FOXP3, IL2RA, IL10, LRBA, MYO5B.	Molecular diagnosis was achieved in 66/207 patients. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations. Genetic characterization of VEO-IBD will help broaden knowledge of the phenotypic spectrum of inherited intestinal disorders. Identifying ke genes may help in creating new therapeutic targets for patients suffering from chronic intestinal diseases.	Study needs to be validated prospectively in an independent cohort of patients.	Level IV, High Quality

Summary and Implications

Genes most notably with identified mutations include IL10RB, LRBA, MEFV
Repeated identification of similar genetic patterns suggests that these associations are relevant
The predominance of observational designs highlight the need for larger, multi-center, and more diverse studies

Overall, this research is significant because it advances knowledge of disease pathophysiology, supports the development of targeted diagnostic and therapeutic strategies, and provides insight on future VEO-IBD cases and prevalence.

Conclusion

The evidence reviewed demonstrated consistent findings across multiple studies.
Most articles were classified as Level IV cohort studies along with several Level VI case studies emphasizing the need for further study with improved control.
Higher-quality studies within this review further strengthen reliability although limitations such as single-center designs, small sample sizes, and reduced generalizability must be considered.
While causation cannot be definitively established due to the predominance of observational and descriptive designs, the consistency of outcomes across studies provides a strong foundation for evidence-informed nursing practice.

Micro-Credential Program Takeaways

The Micro-Credential program allowed me to explore this specific area of IBD while also teaching me how to professionally perform research analyses. Throughout my time at QU, I knew I wanted to continue learning and advancing my nursing degree, but no minor really stuck out to me. When I learned about the opportunity to facilitate my own research project, it was exactly what I wanted. I have learned the importance of evidence-based practice and how staying up to date with the newest data can make an impact in patients treatment plans and how I can be aware of this in my future nursing profession.

Professional Application

"My VEO-IBD project is meaningful to my future in pediatric nursing because it allowed me to explore how genetic mutations and early disease processes can impact children with inflammatory bowel disease at a young age. Researching very early-onset IBD strengthened my understanding of the complex medical, developmental, and emotional needs these patients and families face. Since I have a strong interest in pediatric IBD, this project deepened my passion for caring for children with chronic gastrointestinal conditions and reinforced my goal of providing compassionate, evidence-based nursing care while supporting families through challenging diagnoses and long-term treatment journeys." - Emily Whitters '26

For Further Discussion

This serves as an overview of the project and does not include the complete work. To further discuss this project, please email Emily Whitters.

Micro-Credential Overview

Designed for current undergraduate students at Quinnipiac, the Undergraduate Nursing Research Distinction micro-credential, a Level II Badge, recognizes that students have demonstrated ethical standards for the protection of human subjects in research. Selected elements of the research process may be completed under the guidance of an experienced research faculty mentor. At the culmination of the program, students will collaborate with nurses or other healthcare professionals to share their research or apply scientific evidence through a poster, podium presentation or publication.

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