Structural Variants in Severe COVID-19: Clinical Impact Assessment

Round 1

Reviewer 1 Report

There are errors related to automatic syllable separation (Nu-43 cleotide, clin-115 ically).

Inconsistent use of:

COVID, Covid-19, COVID-19 → Use only for patients treated in the ICU with COVID-19

treated in the ICU→ use patients treated in ICU

It clearly reflects the focus on structural variants and their relationship to severe COVID-19, as well as the intention to assess their clinical impact. However, it could benefit from a minor adjustment to improve clarity and align with standard editorial style in biomedical journals. For example, replacing the semicolon with a colon and using more direct wording ("clinical impact assessment") would make the title flow more smoothly and be more standardized, without altering its scientific meaning.

Author Response

Thank you for your time and positive remarks. We agree with the reviewer's comments and have made changes accordingly. 

Reviewer 2 Report

The manuscript entitled “Structural variants in severe COVID-19; assessing clinical impact” represents a retrospective study, which sought to identify rare structural changes (exonic CNVs and SNVs) in a severe COVID-19 cohort from Sweden. In addition to whole-exome sequencing, the authors obtained a wide list of clinical symptoms accompanying disease course to evaluate a possible relation of these clinical phenotypes to the presence of rare CNVs. The authors provided a detailed characteristics of the studied sample, methods used, pipeline of the study, etc. in Supplementary Materials. However, the identified CNVs and SNVs cannot be directly linked with COVID-19 severity and pathogenesis but to the exaggerated overall frailty of CNV-containing persons, which is mentioned by the authors. The manuscript contains the necessary tables and Supplementary data.

However, certain issues need to be clarified:

1. It is of relevance to indicate the chromosomal positions of “a CNV spanning a COVID-19 implicated gene” (in Table 1 or in Supplementary). In addition, I suggest including the names of the genes, in which the significant CNVs are located and to include the number of examined individuals (in Abstract).
2. It is required to check line 159 on page 4 (notes to the Fig. 1). It seems that one asterisk is absent.
3. Table 1 lacks notes, i.e., all abbreviations should be explained in notes. Why have the authors used red color of the font for Louef equal to 0.27? In addition, Table 3 also requires notes.
4. The authors have identified 61 deletions (in 205 patients), which number was diminished to 11 CNVs (in 14 patients). However, it remains unclear when the authors split the sample into two groups, what was the sample size of “CNV group” and “patients without a potentially damaging CNV”, it should be indicated.
5. The authors reported in Materials and Methods that three pairs of first-degree relatives were also included. The question arises if all the relatives contained the same CNV (for example, in the GALC gene)? What was a rationale for the inclusion of relatives in the analysis?
6. It remains inconclusive, why the authors have used parametric tests for the statistical analysis? Since the study sample is of moderate size, the checks for normality distribution of all examined quantitative variables (such as creatinin level, NT-proBNP) have to be made prior choosing statistical criteria.
7. The results section seems to be overloaded with discussion points. The article will benefit if the authors transfer discussion issues from the Results to the Discussion section.
8. What is a relevance to compare patients with detected CNV versus without CNV? The authors have only examined the presence of structural changes in the exome; however, other rare CNVs can be also present in the remaining group of patients without exonic CNVs and may also have a significant effect on changing gene expression. Therefore, I suggest to clarify this issue in limitations.
9. A paragraph with limitations is required to be added. For example, mentioning moderate sample size, small proportion of patients with identified clinically significant CNVs (N = 14), absence of group of comparison (for example, mild-severity COVID-19 course) is required.
10. The explanation for NT-proBNP (in Abstract) has to be provided after the first mentioning in the text.
11. Please increase the quality of Table 2.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf