Using Precision Medicine to Disentangle Genotype–Phenotype Relationships in Twins with Rett Syndrome: A Case Report
, Ella Goodman-Vincent 1,2,3, Samiya Chishti 1,2,3, Ruben Bonilla Guerrero 4, Federico Fiori 1,2,3, Shashidhar Ameenpur 1,2,3, Leighton McFadden 1,2,3, Zvi Zahavi 5 and Paramala Santosh 1,2,3,*
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
I read with interest your study. I suggest minor revisions: The study involves only one pair of twins, which limits the generalizability of the findings: it is in other world a case report. It would be beneficial to specify starting from the title. More details are needed on the rationale behind choosing buspirone, its dosage, and the exact timeline of administration relative to the observed changes in HRV and clinical symptoms. The article lacks a detailed description of the statistical methods used to analyze the HRV data and clinical scores. Providing information on statistical tests, confidence intervals, and significance levels would improve the robustness of the conclusions. While the improvements in HRV metrics and clinical scores for Twin A post-buspirone treatment are promising, the clinical significance of these changes should be discussed. Are these changes sufficient to impact the quality of life or long-term outcomes for RTT patients? Explore and discuss potential mechanisms by which buspirone may influence autonomic flexibility and HRV. Is there existing literature that supports these findings? The discussion around the rs6265 BDNF polymorphism could be expanded to include more detail on how this polymorphism affects neurodevelopment and autonomic regulation, with references to relevant literature.
Author Response
Please see attached responses to Reviewer 1 document
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsRett syndrome is a rare genetic neurological and developmental disorder. This disorder affects brain development and causes a progressive loss of motor skills and language.
The precision study disentangles the genotype-phenotype relationship in RETT syndrome is quite interesting.
Introduction: The introduction is appropriate.
Material & Method: The M& M is elaborate and easy to understand.
Minor Revision:
The author should add information about Buspirone.
Results:
Minor Revision:
On Page 6 : Initiation of Buspirone:
The author has used Buspirone in twin A . The author should mention the importance of buspirone, they should reference previous study that had reported the importance of buspirone in treating anxiety and respiratory disorder.
Major Revision:
1) Genotyping results need to be validated:
Did the author validate through other approach the genotyping data? If not before the manuscript is published, the author needs to validate the genotyping results.
2) As the author has observed Pro387_Ser486 delinsGln in both the twins, I would recommend the author add the genotyping result in the supplementary.
3) The genotyping result showed that the MECP2 deletion was pathogenic. The author can model the MECP2 protein structure via Homology modeling and compare the difference in protein structure between control and mutated one.
This same approach could be applied to BDNF. Was there any amino acid change after the variant was observed?
Discussion and conclusion are appropriate.
Author Response
Please see attached responses to Reviewer 2 document
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have reviewed the manuscript which is now improved and ready for publication.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe author has done needful modifications.
