In this manuscript Alawbathani et al. describe nine patients with biallelic ZNFX1 variants with immunodeficiency, through a search in a bio/databank for rare diseases with information from genetic testing of >55,000 individuals.

The manuscript is interesting and deserves to be published. Some minor considerations are expressed below:

When first referring to “our in-house bio-databank” define this databank as “a comprehensive global genotype-phenotype database for rare diseases”, including data about when was this database established and how many samples are available.

Since all samples from the databank were already exome or genome sequenced, this point should be clearly stated in Material and Methods. Instead of start this section mentioning “Genomic DNA was extracted...” just state that “A bio-databank was established...” and give all information about the databank.

Also in Material and Methods, when referring to “Patients Five and Six”, please indicate that this is the classification used in the present study (for example, refer to Table 1), not the original patients identification in the databank.

In Figure 1, the identification “Clinical photographs of Patient Nine (II:3; Family Seven)”, should be II:2; Family Seven. Also, maybe it would be important to modify photographs in order to protect the patient identity.

In the Discussion, authors claim that “Interestingly, Patients One and Two manifested with the most severe clinical phenotypes that included liver, spleen, and kidney involvement, hemophagocytic lymphohistiocytosis, developmental delay, and even death of Patient One.” Nevertheless, according to both Table 1 and Figure 1, as well as according to the Case reports description (Supplementary Information), patient Two, instead of patient One, died. Please verify this point.

Considering the following statement “. Of note, the youngest sibling of Patient Four (III.6, Family Four, SI Appendix, Figure 1) was a heterozygous carrier of the p.(Leu1098Glufs*3) ZNFX1 variant and presented with atypical (mild) clinical features including monocytosis and thrombocytopenia, … This finding suggests that some ZNFX1-related disorder phenotypes may be elicited through haploinsufficiency even in the presence of the wild-type protein..” I wonder if it would not be interesting to evaluate the relatives in this and other affected families. Please comment on that.

This is a revised version of the manuscript by Alawbathani et al. describing nine patients with biallelic ZNFX1 variants with immunodeficiency, through a search in a bio/databank for rare diseases with information from genetic testing of >55,000 individuals.

The authors adequately approached all recommendations of this reviewer. Specifically, they included a mention and better description of the databank previously established, better explained patient’s notation and corrected some of the patient’s misidentifications in the Discussion and Figure 1. Also, it seems that they also adequately answered the queries of the other reviewers. In conclusion, although author’s claim that they do not have access to samples from relatives of the patients in order to provide a deeper examination of the genetic variants observed, I still believe that this manuscript is interesting and deserves to be published in its present version.