PONE-D-20-02423

Genetic landscape of preterm birth due to cervical insufficiency: comprehensive gene analysis and patient next-generation sequencing data interpretation

PLOS ONE

Dear Mrs Volozonoka,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Obul Reddy Bandapalli, MSc, PhD

Academic Editor

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: I Don't Know

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: In this research article by Volozonoka et al. Genetic basis of cervical insufficiency is investigated by performing NGS of genes implicated in cervical functioning in patients with cervical insufficiency. The manuscript is overall well written and the the proposed hypothesis of cervical insufficiency being a subtle form of collagenopathy is well supported. It woulb then interesting to add to the report information on the familial history of the analyzed patients, highlighting whether there were additional cases of cervical insufficiency or collagenopathy-related disorders, that would strenghten the idea of a common genetic basis.

Reviewer #2: Authors performed a genetic study on preterm birth due to cervical insufficiency with the support of systematic literature review and NGS analysis of 21 patients based on these review results.

Systematic review was done in detail and the lists were provided as supplementary files.

Although the number of patients is too low to make any significant conclusion about cervical insufficiency based on findings, especially for rare variants, I believe this study still be publishable for the purpose of using it as a guide and summary of reviewing the published papers associated with cervical insufficiency. For that purpose, especially for the genetic findings the tone of the paper couldn’t/shouldn’t be too assertive. Authors did already a good job for being NOT assertive for the findings on 21 samples.

I have some additional comments and suggestions;

In the manuscripts authors indicated that (line number 399-401)“The sequencing resulted in a median coverage depth of 135±38× of the target 400 region, with 94.4% of target regions being covered at least 10 times and 89.7% being covered 401 at least 20 times.”

What about the depth of coverage for rare deleterious variants, if they can mention this in that section, it would be very useful.

Line 60, "Sention", it would be useful to provide a reference in parenthesis as it is citing the kits. Example:(USA, CA)

Line 62, Please cite BWA-MEM algorithm. Although it is very well-known algorithm in the field, for the readers who are not familiar, it is needed to be cited.

Line 75, CADD score threshold was not mentioned, usually it is 15 and higher for pathogenic variants. It would be better to write the threshold, since thresholds for other filters were indicated.

Line 76, PHRED Score >10 is too low, which means probability of 1 in 10 of incorrect base call, usually 30 is and higher is preferred. I would recommend strongly to adjust it to 30 for this.

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Reviewer #1: No

Reviewer #2: No

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Genetic landscape of preterm birth due to cervical insufficiency: comprehensive gene analysis and patient next-generation sequencing data interpretation

PONE-D-20-02423R1

Dear Dr. Volozonoka,

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.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Obul Reddy Bandapalli, MSc, PhD

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: I Don't Know

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: (No Response)

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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