The draft describes the molecular characterization of a Spanish cohort of patients with MECP2 duplication syndrome (MDS). The study had multiple goals, including diagnostic and molecular delineation; determination of size, origin and location of duplication; impact on gene expression; and genotype-phenotype correlations. The authors concluded that (a) complete duplication of both MECP2 and IRAK1 is necessary for a proper MDS diagnosis and (b) location of the duplication might be related to phenotypical severity.

Although the study involved only 21 subjects, 19 boys and 2 girls, it is still a valuable contribution to the field considering the relatively low prevalence of MDS and the small number of publications on the subject. The authors used a variety of complementary molecular techniques for evaluating the characteristics of the patient population, that included a custom-designed MLPA assay for delineating the minimal duplicated region. Other methods were more conventional (e.g., XCI, qPCR); however, their integration was thoughtful. The conclusion that only complete duplications of both MECP2 and IRAK1 are necessary for the MDS phenotype is an important finding. However, other conclusions (e.g. implications of duplications’ locations) should be considered more preliminary given the relatively small cohort. Furthermore, the division of phenotypical features between clinical and behavioural is confusing. The listed behavioural abnormalities are clinically relevant and, in HPO, are classified under Abnormality of nervous system physiology as well as others in the “clinical” category on Table 1 (e.g. intellectual disability). Also, poor eye contact is usually linked to impaired social interaction. In general, conclusions should be qualified considering the small sample and incompleteness of some parameters. Careful proofreading is also encouraged.

The draft describes the molecular characterization of a Spanish cohort of patients with MECP2 duplication syndrome (MDS). The study had multiple goals, including diagnostic and molecular delineation; determination of size, origin and location of duplication; impact on gene expression; and genotype-phenotype correlations. The authors concluded that (a) complete duplication of both MECP2 and IRAK1 is necessary for a proper MDS diagnosis and (b) location of the duplication might be related to phenotypical severity.

The initial review recognized the multiple strengths of the study, including its main conclusions. However, it also pointed out that there were weaknesses that included confusing nomenclature on phenotypical features, limited acknowledgement of the study pitfalls (e.g., small sample, data incompleteness), and poor grammar.

The authors have been responsive and modified several sections, including deleting or moderating some conclusions. Nonetheless, one of the problematic statements remains. Peters and colleagues acknowledged the limitations of using a severity scale designed for Rett syndrome, although they did not mention recurrent infections as an important omission. A major issue the authors did not address is grammar; throughout the manuscript there are multiple awkward sentences. They make the Discussion section particularly difficult to read.

The draft describes the molecular characterization of a Spanish cohort of patients with MECP2 duplication syndrome (MDS). The study had multiple goals, including diagnostic and molecular delineation; determination of size, origin and location of duplication; impact on gene expression; and genotype-phenotype correlations. The authors concluded that (a) complete duplication of both MECP2 and IRAK1 is necessary for a proper MDS diagnosis and (b) location of the duplication might be related to phenotypical severity.

The R1 version was improved but it still included confusing nomenclature on phenotypical features, limited acknowledgement of the study pitfalls (e.g., small sample, data incompleteness), and poor grammar. This revision, version R2, addresses many but not all these issues. Some sections are still grammatically challenging and present a biased description of the study by Peters and colleagues. These authors acknowledged the limitations of using a severity scale designed for Rett syndrome, so the statement that “a specific MDS severity scale would be more appropriate than the RTT severity scale, as the RTT phenotype does not exhibit e.g., recurrent infections” misrepresents the aforementioned study.