Dear the Author

Reviewer has evaluated a paper by Adham et al. describing a family with classical EDS cause by an Arg312Cys COL1A1 variant. The observation is interesting and the manuscript is well-written. Several issues have been found to clarify the findings and improve the paper.

Page 1, Figure, the signs such as “COL3A1 +/- or +/-“ would be unclear. What did the authors mean by “+” or “-“, relevant variant(s) positive or negative?

If available, a facial photograph is recommended to be presented.

Why was the patient treated with celiprolol? How do the authors think the validity of using celiprolol on this patient with COL1A1 pathogenic variant not COL3A1 variant?

Did she undergo intravascular or surgical intervention for some of the arterial episodes? If yes, how was the outcome?

How were the estimated pathogenicity of COL3A1 variant according to ACMG guideline (only mentioned as “benign”, more concretely), several in silico evaluation, and large-scale databases for patients and healthy individuals?

Did the authors perform biochemical analysis of type 3 procollagen to exclude the possibility of involvement of the detected COL3A1 variant (p.Lys1273Arg)?

What kind of platform did the authors use in the gene panel analysis (probably NGS)?

In considering co-segregation of the COL1A1 variant, EDS-related skin/skeletal features, and arterial complications, more clinical information are recommended to be collected such as vascular images of I-2 (asymptomatic aneurysms or dissections), skin/skeletal features in II-2, etc.

Dear the Author

The manuscript has been corrected according to reviewers' suggestions and improved sufficiently.