PONE-D-19-34036

Hypomorphic SI genetic variants are associated with childhood chronic loose stools

PLOS ONE

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript compiles the results of a large multicenter study on the relation between functional GI symptoms in children and 37 variants of the sucrase-isomaltase gene that have been previously characterized at the biochemical and cellular levels in congenital sucrase-isomaltase deficiency (CSID). The study demonstrates a significantly higher prevalence of hypomorphic SI variants in the cases studied than in the general population.

The study supports recent views that heterozygous genotype of hypomorphic SI may be associated with an increased risk of irritable bowel syndrome. The study is properly conducted and impressive in terms of the number of cases studied. The statistical analyses are convincing and the conclusions are sound. The manuscript is clearly written (only lines 95/96 should be rewritten).

I fully agree with the conclusions, have no points of criticism and recommend the acceptance of the manuscript in its present form.

Reviewer #2: The manuscript by Chumpitazi et al assesses the prevalence of variants in the sucrase-isomaltase gene among a cohort of children with chronic diarrhea. The authors find that confirmed or predicted loss of function mutations are more prevalent in the studied population versus a the EXAC reference genomic database. Furthermore, they show that patients with mutations have more diarrhea symptoms than the rest of the patient cohort. The study suggests a potentially interesting possible association between mild chronic diarrhea and SI function in young children. The strengths of the paper are that the patient cohort is taken from multiple different centers / sites and sample genotyping was done in a uniform manner at a central site. The statistics and results, while limited in scope are appropriately done.

1. The major limitation in understanding the significance of these findings, as briefly but insufficiently discussed, is that the functional effect of heterozygosity in the various loss-of-function mutations, and especially the common variants found in these patients remain poorly described and essentially unknown. The authors cite a single case report and a study on 13C breath testing in functional GI disorders (not specifically with known SI genotype), neither of which is sufficient to address the question of SI heterozygosity and enzyme activity. To assess the functional significance requires prospective clinical studies with functional measurements (enzyme/breath testing) correlated to genotype as well as basic cell-based studies assessing heterozygous vs homozygous mutations and function / localization. This should be more clearly part of the discussion and the major limitations of the existing literature (studies of symptom correlation rather than objective enzyme activity, few studies, no cellular studies etc) more straightforwardly stated.

2. In the methods the reference database link should be updated to either Gnomad or the legacy EXAC only data. There should be brief sentence explaining this update.

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Reviewer #1: No

Reviewer #2: No

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Hypomorphic SI genetic variants are associated with childhood chronic loose stools

PONE-D-19-34036R1

Dear Dr. Chumpitazi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Adriana Calderaro

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: My initial review recommended acceptance of the manuscript as it stands and I have just asked for minor edits. These edits have been made in the revised version.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No