Sudden Cardiac Death in Biventricular Arrhythmogenic Cardiomyopathy: A New Undescribed Variant of the MYH6 Gene

Round 1

Reviewer 1 Report

The study describes the case of a patient, who was diagnosed with biventricular arrhythmogenic cardiomyopathy and was found to be bearing a frameshift mutation in the MYH6 gene. This is a novel association. MYH6 mutations have not been implicated in the pathogenesis of ACM before. I have the following comments:

Given the predominant LV involvement (and the genetics result), could the diagnosis be that of dilated cardiomyopathy as opposed to ACM?

Since further family members declined genetic testing, it is premature to establish pathogenecity of the variant on the basis of the proband and her daughter only. In such cases, functional characterization of the variant is necessary prior to attributing the disease to this mutation. I suggest the authors express the variant in a cellular system and investigate if it causes abnormalities (such as protein distribution changes) characteristic of ACM.

Was in silico analysis of the variant performed?

What disease are similar variants in MYH6 reported to underlie?

 

Author Response

Please see the attachment. Thank you.

Author Response File: Author Response.pdf

Reviewer 2 Report

In the manuscript 'Sudden Cardiac Death in Biventricular Arrhythmogenic Cardiomyopathy: a new undescribed variant of the MYH6 gene' submitted by Pedro Garcia Bras and coworkers to Cardiogenetics, the authors have identified a novel MYH6 mutation in patients suffered by SCD / SCA. The manuscript is interesting and is about an interesting case. However, the introduction needs extensions and also some others parts of this manuscripts should be changed.

1.) Please add a OMIM identifier for ACM / ALVC ...

2.) The genetic background of ACM should be explained including relevant references. A good starting point would be the following review article: Insights into genetics and pathophysiology of arrhythmogenic cardiomyopathy. Explain that the majority of ACM patients carry mutations in genes encoding for desmosomal proteins and that in addition patients can carry mutations in other non-desmosomal genes. Because MYH6 is a non-desmosomal sarcomere encoding gene, other relevant non-desmosomal genes like DES, ILK, LEMD2, PLN, TMEM43 should be discussed including relevant references. Especially for patients carrying DES variants several different groups have identified different mutations (e.g. DES-p.A120D, DES-p.L115I or DES-p.E401D) in patients with ACM. Do your patients carry rare variants in one of these genes? If not compare the phenotype of your patients for example with DES mutation carryiers presenting ACM / ALVC.

3.) Please prepare a figure showing the sequencing results of your patients.

4.) Could you shortly introduce the function of MYH6 in cardiomyocytes?

5.) Are different other families known carrying premature stop codons in MYH6 presenting a similar phenotype. Please include relevant references.

6.) Are animal models or cell culture models known for MYH6 mutations? Please discuss.

In summary, I suggest a major revision where the authors should improve the introduction explaining in more detail the genetic background of ACM / ALVC. Although, the authors have not presented any functional data, I think that this manuscript can be fixed for example by presenting the genetic detailed NGS / Sanger sequencing data and a broader discuss of similar cases. Also other genptypes leading to ACM / ALVC like e.g. DES mutations should be discussed by the authors. 

Good luck with the revision. 

Author Response

Please see the attachment. Thank you.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors have significantly altered their manuscript to address all the comments I raised in my first review. I have no further comments. I believe that in its current format the manuscript does merit publication. 

Reviewer 2 Report

Congratulations! The authors have improved their manuscript. 

Mino corrections might be necessary.