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PONE-D-22-07070Genetic variants determine intrafamilial variability of SARS-CoV-2 clinical outcomes in 19 Italian familiesPLOS ONE

Dear Dr. Azzarà,

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PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

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

Reviewer #1: Yes

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Reviewer #1: No

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Reviewer #1: Yes

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5. Review Comments to the Author

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Reviewer #1: Azzará et al. investigated the transmission dynamics of SARS-COV-2 within Italian families whose members responded in different ways to infection, before the availability of any vaccine. To this, they performed a segregation analysis in 19 families of 42 genes involved in immunity and virus enter. They also performed a global statistical analysis. They identified 18 risk variants co-segregating with COVID-positive status and 6 variants with a protective effect. Moreover, 16 variants showed a trend of association to a severe phenotype. The global statistical analysis confirmed positive associations between specific variants and SARS-COV-2 response. The study is interesting, original, and contributes to the search of variants associated with COVID-19 infection and severity. However, they are few concerns with the manuscript in its current form.

- Regarding the global statistical analysis: as the authors acknowledged, the sample size was small for this analysis and some associations could be lost due to lack of statistical power. This needs to be better discussed in the Discussion section as a limitation of the study.

- Page 14, lines 187-188: What did the authors mean by gene mutation rate? Frequency of each variant? If yes, please correct the information in the text since mutation rate is not the same as the frequency of individual variants.

- There are 8 tables (plus 2 figures). Some tables are unnecessary. Table 2 could be added in the Supplementary material and table 7 could be excluded and the information only written in the main text.

- Table 8 (Statistical global analysis of gene variants): This table could be better described and formatted. Are the frequencies shown for the minor alleles? The authors could add OR for each variant. Please check the frequency of the most mutated gene in positive individuals (STAT2). Positive is 0.62% only? And for what variants these frequencies of the most mutated genes in positive and negative individuals are shown?

- Discussion (page 30, line 432): “…whereas it showed a trend for NLRP1 (p=0.093) as a protective gene (data not shown)”. The authors declared that all information was included in the paper; thus, these data not shown must be included in the paper.

- The Discussion section is too long. It could be shortened.

- It would be interesting to cite a recent systematic review and meta-analysis published in Plos One regarding the association of genetic variants and COVID-19:

Genetic polymorphisms associated with susceptibility to COVID-19 disease and severity: A systematic review and meta-analysis. Dieter C et al. PLoS One. 2022 Jul 6;17(7):e0270627. doi: 10.1371/journal.pone.0270627.

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Reviewer #1: Yes: Daisy Crispim Moreira

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Genetic variants determine intrafamilial variability of SARS-CoV-2 clinical outcomes in 19 Italian families

PONE-D-22-07070R1

Dear Dr. Azzarà,

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

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Kind regards,

Cinzia Ciccacci

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: