Comments on abstract, title, references

This is very interesting and clinically relevant report of the autosomal dominant NF-KB1 related phenotype. The abstract clearly contains all the different sections with targeted aims, robust methodology and key conclusion. The title resume the key features of the report and it sounds interesting. references are relevant and cited correctly.

Comments on introduction/background

The introduction is relevant with logical progression and historical known background. The authors clearly define the gap and adopt an appropriate hypothesis (''However, these reports covered only a few cases each, and an overview and understanding of the broader clinical spectrum of this NF-kB1–related condition is still lacking.''). They also match an appropriate method and a suitable subject group presenting different mutations in the pathway studied in this report with a wide range a phenotype related. their conclusion is matching with the introduction and answer their questions. in conclusion the author highlights an important finding and the introduction is clear, concise and easy understood.

Comments on methodology

● Is the process of subject selection clear? Yes, the selection of subject is clear, and method of investigating is detailed for individuals and for each variant.

● Are the variables defined and measured appropriately? Yes, the chosen subjects are found worldwide and are mostly published. On the basis of their predicted effect, localization, allele frequency, supportive functional studies and inheritance and segregation, the measure is then well defined and appropriate. They also use different tools to predict the impact of missense changes.

● Are the study methods valid and reliable? YES, the used different methods with cell types and transfection tools to make the methods valid and reliable.

● Is there enough detail in order to replicate the study? The investigators did not mention the number of the replication of experiences established.

Comments on data and results

● Is the data presented in an appropriate way? YES, it highlights the key elements.

● Tables and figures relevant and clearly presented? Yes, they are clear. However, some abbreviations are not defined in the legend and a wrong full word description of GAPDH in the fig 1 rather in the fig2.

● Appropriate units, rounding, and number of decimals? YES

● Titles, columns, and rows labelled correctly and clearly? Yes, except for the wrong place of GAPDH IN FIG 1.

● Categories grouped appropriately? YES, categories grouped appropriately. However, I liked to see a figure with correlation between Clinical and biological findings with mutations.

● Does the text in the results add to the data or is it repetitive? It is descriptive, clear and concise.

● Are you clear about what is a statistically significant result? Yes, data are statistically significant and effective (using the P value the std deviation the mean average ...).

● Are you clear about what is a practically meaningful result? Yes, the results are statistically meaningful and could contribute to help diagnoses, management and even for therapeutically approaches.

Comments on discussion and conclusions

● Are the results discussed from multiple angles and placed into context without being overinterpreted? Yes, the authors discussed the findings using age, clinical, biological and therapeutically. However, they didn't discuss the relevance of mutations described on the report from these different angles.

● Do the conclusions answer the aims of the study? Yes, they made clear conclusions responding their objectives.

● Are the conclusions supported by references or results? Yes, they used some references to support their conclusions.

● Are the limitations of the study fatal or are they opportunities to inform future research? Absolutely Not. They presented the limitation of the study explicitly and aware others to make a good diagnosis and informing future research.

Overall statement or summary of the article and its findings in your own words

The report is interesting and gives insight to the diagnosis, management and therapeutically approaches of a wide range of patients with heterogenous symptoms of NF-kB pathway dysregulation.

Overall strengths of the article and what impact it might have in your field

The paper presents many patients worldwide with different mutations in the NF-KB pathway leading to different symptoms. the authors try to find the adequate diagnosis and treatment from a comprehensive clinical description of patients.

Specific comments on weaknesses of the article and what could be done to improve it

●Major points in the article which needs clarification, refinement, reanalysis, rewrites and/or additional information and suggestions for what could be done to improve the article. The authors should add a correlation for mutations causing symptoms.

●Minor points like figures/tables not being mentioned in the text, a missing reference, typos, and other inconsistencies. 1-Some abbreviations in the fig 1 are missing. 2- GAPDH misplaced.