Review for 10.1186/s12876-025-04041-4 (2025)

Title: Comprehensive Evaluation of Clinical Phenotypes and Pathogenic Features in Late-Onset
Monogenic Inflammatory Bowel Disease: A Comparative Study with Infantile-Onset Cases
Version: 1 Date: 31 Mar 2025
Reviewer:  Fabienne Charbit-Henrion
Reviewer's report:
Article : Comprehensive Evaluation of Clinical Phenotypes and Pathogenic Features in Late-
Onset Monogenic Inflammatory Bowel Disease: A Comparative Study with Infantile-Onset
Cases
The authors conducted a retrospective analysis of the literature published between 1990 and
2023. They compared the characteristics of patients with late-onset monogenic inflammatory
bowel diseases (LO mIBD, over 16 years) with infantile onset (under 2 years). 436 IO-mIBD
and 110 LO-mIBD cases were included and analyzed. It is a comprehensive work and useful,
summarizing many small reports and allowing interesting conclusions to be drawn. Some points
(below) could be improved.
General suggestion: by including only patients with an IBD phenotype, the authors have
excluded patients with monogenic enteropathies with a celiac-like or refactory celiac-like
phenotype. These patients could be interesting to compare, especially in terms of age of onset
and pathophysiologically disturbed pathways.
Methods: What is TNPS (line 10)? I think the authors should refer to either TGPS targeted gene
panel sequencing or TNGS targeted next-generation sequencing, not both, as these two terms
refer to the same technique.
Results
The authors state that the total number of monogenic IBD patients was n=938, of which 546
patients had IO or LO, which means that 392 patients with mIBD with an age of onset between
2 and 16 years were not characterized. Although it would change a bit the message of the article
somewhat, it would be interesting to compare them with both IO and LO-mIBD patients. Do
monogenic patients scatter along a spectrum according to age of onset?
Treatments: Supplementary Figure 4 does not make it easy to apprehend the individual treatment
efficacy for each gene defect. The number of cases treated with targeted therapies is inevitably
low, as these treatments have not been available for a long time, but the authors should try
to consider how to modify Suppl Fig 4 to better capture the crucial improvement in care that
targeted therapies such as JAKinibs, anti-IL1R or CTLA4 analog can bring to some (otherwise
refractory) patients. I would suggest moving Suppl Fig 4 to main text. If space needed, Figure
3 A and B could be moved to supplementary data, and only Figure 3 panel C could be retained.
Discussion
Overall, the Discussion is rather long and a bit repetitive. The authors could strengthen their
messages by synthetizing the Discussion.
Lines 15-16 : the authors wrote “These findings indicate distinct inheritance patterns between
IO- and LO-mIBD. Specifically, the AD defects common in LO-mIBD include GUCY2C,
CTLA4, SYK, etc.” More than a different inheritance pattern, LO-mIBD patients have mutations
in genes that are different from IO-mIBD patients. The authors may want to emphasize the need
to offer specific genetic counselling to LO-mIBD patients as many have a 50% risk of recurrence
in their offspring.