Natural Course of IQSEC2-Related Encephalopathy: An Italian National Structured Survey
, Lidia Boasiako 1,2, Diego Lopergolo 3,4,5, Maria Altamura 1,2, Caterina Fazzi 1,2, Roberto Canitano 6, Salvatore Grosso 7,8, Ilaria Meloni 9,10, Margherita Baldassarri 9,10,11, Susanna Croci 9,10, Alessandra Renieri 9,10,11, Mario Mastrangelo 12,13 and Claudio De Felice 1,2,*Round 1
Reviewer 1 Report
The authors present a thorough phenotypic analysis of a rare genetic cause of intellectual disability, IQSEC2-related encephalopathy. This careful and well-researched description of 19 patients will help to further understanding of this underdiagnosed disorder.
Note: I did not find the supplementary figures included in either the main manuscript pdf or the "non-published material" pdf.
A few specific comments:
Section 3.1 - consider displaying all incidence and prevalence figures in the same format (e.g. 0.07 per 100,000 for IQSEC2, 3.2 per 100,000 for US RTT) to allow for direct comparisons.
Section 3.2 - as noted above, supplemental table S2 was not available for review. The term "co-mutation" is imprecise as every individual carries numerous mutations in most of our genes; what you are referring to is a pathogenic variant in an additional gene. Later, in the discussion (lines 775-776) the authors state, "Interestingly, about one third of patients harbored coexisting co-mutations in other genes." However, this rate will vary greatly depending on the diagnostic testing utilized (e.g. gene panel vs exome vs genome sequencing).
Figure 1 - please explain how the p.Trp742* nonsense variant is considered a mild mutation; one would expect it to be considered severe as are the other nonsense and frameshift variants.
There are a few awkward sentences that need rephrasing (e.g. lines 67-68).
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This is a manuscript about an Italian National structured survey about natural course of the IQSEC2-related encephalopathy, in which most information was obtained through the interview of parents/caregivers. Although this study contains too vast amount of data, it seems informative and educational for diagnosing IQSEC2-related encephalopathy, sharing the clinical features with RTT syndrome.
There are a few comments;
1. L.273 and 580; What is the definition for IQSEC mutation severity classification. Although the author refers two papers, #47 and 48, it is difficult to find it. Is the severe mutation a variant that cause severe phenotype, or a variant of nonsense or splicing?
2. L.627; Is “RTT and RTT patients” incorrectly spelled as RTT and RTT-like patients?
Author Response
Please see the attachment
Author Response File: Author Response.pdf
