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The authors have addressed all of the reviewers' and editor's concerns and comments. I am happy with the current version, and in my opinion, the manuscript is ready for publication.
1. Suggested abstract revision (based on Reviewer 1’s suggestion): “More than 50% of congenital hearing loss is hereditary, in which the majority form is non-syndromic. In the present study, ..... the Republic of North Ossetia–Alania (RNO–Alania) were assessed. ....These estimates correspond to the literature data on the fraction of recessive genetic forms of hearing loss within the affected population. The importance of this study consists not only in the estimation of the most prevalent pathogenic genetic changes in the Ossetian cohort of patients which could be useful for the public health but also in the genetic counselling of the affected families with regard to the high allele frequencies of revealed pathogenic variants as well as to the assortative mating in community of people with hearing loss.
2. Please be consistent whether the authors are using NSNHL (Abstract, Introduction, Result, Discussion) or HSNHL (Material & Methods, Discussion, Tables) to describe their patient group.
3. Introduction, page 2 line 64-65: “The timeliness of taking measures to rehabilitate children with hearing impairment determines the success...”
4. Introduction, page 2 line 74: “...and counts account for 5.6% of the cases...”
5. Introduction, page 3 line 90: “...,the frequency of carrying variant c.245G>A was 1:44 Chuvash,...”
6. Introduction, page 3 line 99-100: “...and allelic genetic heterogeneity of hereditary nonsyndromic hearing loss NSNHL in the Republic of North Ossetia–Alania (RNO-Alania) and...”
7. Material & Methods: “Written informed consent was obtained...”
8. Result, page 5 line 180: “... according to the All-Russia Census,...”
9. Result, page 5 line 192: “...it should be noted that all patients carrying that genotype were...”
10. Discussion, page 7 line 252-253: “Comparison of the GJB2:c.35delG and GJB2:c.358_360delGAG variants frequencies we revealed no statistically significant difference...”
My remarks were taken onto account in the revision. The reporting is clear. It corresponds to the publication standards. I recommend accept this work for publication.
I have no more comments.
Conclusions of the work are well stated and limited to supporting results on genetic forms of hearing loss within the population studied.
The text was updated. I have no more major remarks. However due to the updates some logics of the presentation in the Abstract was distorted.
I suggest move the starting phrase in the Abstract "The importance of this study consists not only in the estimation ..." to the concluding part.
Please start the Abstract by a common phrase about the problem of nonsyndromic sensorineural hearing loss study.
Give the abbreviation 'RNO' in full in the Abstract (now it is shown in the Introduction only).
All my suggestions were addressed in the revised version.
No comment
No comment
1. The authors wrote "...consisted of 109 individuals from 93 unrelated families, 82 Ossetians, 12 Russians, 3 Ingush, 2 Avar and 9 people of other ethnicity" (Material & Methods, lines 104-105). Please add descriptions on how the authors determine the ethnicity of the patients.
2. Please add page numbers.
[# PeerJ Staff Note: Please ensure that all review and editorial comments are addressed in a response letter and any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate. #]
This work highlights genetics background of nonsyndromic sensorineural hearing loss based on unique population sample.
The problem of genetics background of this disease is important. It fits to the journal scope.
The paper is well-structured.
However I have some remarks on the material presentation.
In the Abstract (Line 24) it is necessary note the importance of the problem of hereditary nonsyndromic sensorineural hearing loss - add new phrase.
At the end of the Abstract need comment on “informative value of the diagnosis” (line 37) - why this parameter is important, how it compared with other genetic studies. “36.7%” looks like not high number. Add a sentence.
Overall, the clinical picture of the patients included into the study is not well-described. It is strongly recommended to extend the description of phenotypic peculiarities of the course of disease, e.g the age of onset, the degree of hearing loss.
Research questions on gene polymorphism detection are relevant to the study. Experimental design of genetic testing corresponds to the standards.
Please comment: is it possible to estimate the prevalence of hearing loss in the studied population based on the data collected during the study?
Molecular background of nonsyndromic sensorineural hearing loss was revealed for GJB2 gene pathogenic variants. The underlying data have been provided. The pathogenic variants of the GJB2gene were identified.
It is recommended to name all the CNV based on the novel ISCN-20 nomenclature since they were identified by molecular cytogenetic method (MLPA).
First phrase in the Abstract needs more detail about the importance of the hearing loss problem. The conclusion in the Abstract also should be more clear stating importance of the diagnostics. I suggest add a phrase there.
Avoid to cite 3 and more references together. “[1-2]“ is acceptable, but “[13-22]” and “[13-21]” are not (line 77 and line 80).
Either remove redundant references, or cite it separately (it is about genetic causes for the populations - give these references in the next paragraph.
Subsection titles should be in Italic or bold font. It differs now in the sections.
Line 161: the formula should be in Italic.
Line 208 - looks like redundant section title. Please fix it. Or start not from number 3.
See lines 259 and next line 286. These section titles are not readable.
Dr Petrova and colleagues studied 109 NSNHL patients and found several variants in distinct genes. I find the paper interesting in terms of the characterization of the cohort presented. However, the text is not easy to understand in some parts, mainly in the Discussion section. The authors are invited to rephrase some of the sentences to make the text clear and easy to read.
Other comments and suggestions:
Line 245: This section is not easy to read.
Line 268: Please explain the sentence “A similar or the same hemizygous deletion chrX:(81676507_81728494)_(81728798_81866106)¬del (hg18) was identified in another male patient in whom pathogenic variants in the GJB2, GJB3 and GJB6 genes were not detected.”
Line 294- According to the authors “the variant c.823G>C (rs183969516) was described earlier and listed in gnomAD.”. Was it described in the literature? If so, the reference should be mentioned.
Line 296: The results of the pathogenicity prediction (e.g. using CADD) for the new variants reported in the paper should be included.
Other minor comments:
Line119: Change “Еhe” to The
Line 194: Change “Table 1” to Table 3
Line 222: Change “ClinCar” to ClinVar
Line 142: The number of samples analysed by Whole-exome sequencing should be mentioned in the Material and Methods section.
no comment
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