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: 02 Apr 2025
Reviewer's report:
This paper is a well thought-out and wellwritten systematic review of infantile onset and late
onset monogenic IBD. The clinical conclusions are clearly presented, and the statistical analysis
is convincing and robust.
My main concern arises from the genetic analysis, which pools data from 1990 to 2023. This
means combining genetic data from completely different eras. More importantly, genetic data
from before 2015 and after 2015 differ significantly, as the introduction of ACMG criteria
for variant classification had a major impact on many genetic conditions. Papers published
before 2015 typically reported variants or mutations in genes, but their roles must now be re-
evaluated according to current standards. For example, in many monogenic autoinflammatory
conditions, variants reported in the original papers, where a gene was first discovered, may still
be considered pathogenic, while others are now classified as of unknown significance or benign.
After 2015, population databases such as ExAC and gnomAD, as well as other tools, have been
instrumental in this reclassification process. For this reason, I appreciated the effort to focus on
the top 14 genes, but even for these genes, there may be a mix of variants that, according to
today’s standards, would need to be individually reclassified. I would suggest maintaining the
clinical conclusions, but the correlation between genes, their reported variants, and the clinical
outcomes must undergo intense scrutiny in terms of variant classification.
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: 02 Apr 2025
Reviewer's report:
This paper is a well thought-out and wellwritten systematic review of infantile onset and late
onset monogenic IBD. The clinical conclusions are clearly presented, and the statistical analysis
is convincing and robust.
My main concern arises from the genetic analysis, which pools data from 1990 to 2023. This
means combining genetic data from completely different eras. More importantly, genetic data
from before 2015 and after 2015 differ significantly, as the introduction of ACMG criteria
for variant classification had a major impact on many genetic conditions. Papers published
before 2015 typically reported variants or mutations in genes, but their roles must now be re-
evaluated according to current standards. For example, in many monogenic autoinflammatory
conditions, variants reported in the original papers, where a gene was first discovered, may still
be considered pathogenic, while others are now classified as of unknown significance or benign.
After 2015, population databases such as ExAC and gnomAD, as well as other tools, have been
instrumental in this reclassification process. For this reason, I appreciated the effort to focus on
the top 14 genes, but even for these genes, there may be a mix of variants that, according to
today’s standards, would need to be individually reclassified. I would suggest maintaining the
clinical conclusions, but the correlation between genes, their reported variants, and the clinical
outcomes must undergo intense scrutiny in terms of variant classification.
Please review this paper.
user
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: 02 Apr 2025
Reviewer's report:
This paper is a well thought-out and wellwritten systematic review of infantile onset and late
onset monogenic IBD. The clinical conclusions are clearly presented, and the statistical analysis
is convincing and robust.
My main concern arises from the genetic analysis, which pools data from 1990 to 2023. This
means combining genetic data from completely different eras. More importantly, genetic data
from before 2015 and after 2015 differ significantly, as the introduction of ACMG criteria
for variant classification had a major impact on many genetic conditions. Papers published
before 2015 typically reported variants or mutations in genes, but their roles must now be re-
evaluated according to current standards. For example, in many monogenic autoinflammatory
conditions, variants reported in the original papers, where a gene was first discovered, may still
be considered pathogenic, while others are now classified as of unknown significance or benign.
After 2015, population databases such as ExAC and gnomAD, as well as other tools, have been
instrumental in this reclassification process. For this reason, I appreciated the effort to focus on
the top 14 genes, but even for these genes, there may be a mix of variants that, according to
today’s standards, would need to be individually reclassified. I would suggest maintaining the
clinical conclusions, but the correlation between genes, their reported variants, and the clinical
outcomes must undergo intense scrutiny in terms of variant classification.
assistant