Cardiac Phenotype Associated with Two Heterozygous LMNA Variants

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Siikjärvi and colleagues report a case of a Finnish woman who carried two heterozygous likely pathogenic variants in the LMNA gene and presented with dilated cardiomyopathy and arrhythmic rhythm. My comments are as follows:  

Major Comments:

1. The reason for the cardiac phenotype is still unclear. Is it due to viral myocarditis, rhythm disorders, or actual dilated cardiomyopathy (DCM)? The authors should draw a conclusion on what they believe is the underlying pathology, as the current manuscript is quite descriptive.
2. Given that the patient presented at the clinic with rhythm disorders, was a next-generation sequencing (NGS) screen for arrhythmic genes performed, in addition to the DCM panel? Were any titin variants identified?
3. It is most likely that these variants are in cis configuration, since the children did not inherit these variants. The authors could consider adding this statement on pages 5, lines 133-138.

Minor Comments:

1. The pedigree figure is incorrectly labeled as Figure 5.
2. Figure 2 does not include arrows.

 

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The case report 'Cardiac phenotype associated with compound heterozygous LMNA variants' is interesting also to a broad readership. However, I think there are some changes and extensions necessary, before this manuscript should be published:

1.) Line 24: Lamin A and C are not really part of the nuclear membrane. They form a mesh associated with the nuclear membrane. Please correct this.

2.) Please add an OMIM identifier for LMNA associated cardiomyopathies.

3.) I would shortly summarize the genetic background of DCM within the introduction. For example, it is known that mutations in TTN, RBM20 or DES cause also cardiomyopathies. You could insert the following references for these three major DCM genes: Especially, since DES is also like LMNA encoding an IF protein, I think you should introduce DES (and the other two genes).

'Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy’ Nature Genetics 2002.

‘Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20’ Hum Mutat 2020.

‘Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect’ J Mol Cell Cardiol 2016.

4.) I understand that the DNA of the father is not available. But you can use long range DNA sequencing for example by nano pore sequencing to investigate if the two missense mutations in LMNA are on the same chromosome. This should not be a large experiment.

5.) Please add a detailed table, where you list all other genetic variants identified in your screen. Why were these variants excluded as disease causing variants?

6.) Please add a table where you summarise the NGS gene panel, which you used in your study.

In summary, I suggest a major revision for this manuscript.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

No further comments

Author Response

Thank you very much. 

Reviewer 2 Report

Comments and Suggestions for Authors

Unfortunately, the authors have not addressed two of my major points. A table with the additional genetic variants is really necessary and in addition the point with the long-range sequencing (Nanopore Sequecing) is also not addressed. Therefore, I still suggest a major revision or to reject this manuscript.

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf