Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy

Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy

Accepted Manuscript Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy Andreas Brodehl, Hendrik Mi...

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Accepted Manuscript Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy

Andreas Brodehl, Hendrik Milting PII: DOI: Reference:

S0022-2828(17)30023-8 doi: 10.1016/j.yjmcc.2017.01.012 YJMCC 8514

To appear in:

Journal of Molecular and Cellular Cardiology

Received date: Revised date: Accepted date:

30 June 2016 18 January 2017 20 January 2017

Please cite this article as: Andreas Brodehl, Hendrik Milting , Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yjmcc(2016), doi: 10.1016/j.yjmcc.2017.01.012

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ACCEPTED MANUSCRIPT Functional studies can contribute to predict the pathogenicity of a novel mutation for cardiomyopathy

Andreas Brodehl and Hendrik Milting

First of all, we thank Dr. Bermúdez-Jiménez and Dr. Jiménez-Jáimez for their comments (Bermúdez-Jiménez und Jiménez-Jáimez 2016) to our study

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characterizing the novel DES-p.L136P mutation in a patient with dilated cardiomyopathy (DCM) (Brodehl et al. 2016).

We fully agree with the authors of the letter that a co-segregation analysis is an important tool to validate the pathogenic and clinical impact of sequence variants as previously shown in many cases (Merner et al. 2008; Gerull et al.

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2013). In the guidelines for classification and interpretation of human genetic sequence variants of the ‘American College of Medical Genetics and

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Genomics’ (ACMG), co-segregation is a ‘supportive or strong’ criterion – dependent on the degree of co-segregation (Richards et al. 2015). However, these guidelines consider also several different criteria like

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‘functional analysis’, ‘in silico prediction’ and ‘absence in controls’ to define the impact of genetic sequence variants. Based on these different criteria, a

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genetic sequence variant can be classified into five categories: Pathogenic

(1).

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(5), Likely pathogenic (4), Unknown significance (3), Likely benign (2), Benign

The absence of co-segregation of a particular variant is alone not a sufficient

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criterion for the classification as ‘Likely benign’ or ‘Benign’ since cosegregation analyses have also some limitations in clinical practice: I.e. families in industrialized countries are often too small, DNA samples from family members might not be available and the clinical evaluation of deceased or healthy members might not be possible. In addition, numerous genetic variants are not fully penetrant complicating the interpretation of sequence data. And finally, in cases of de novo mutations a family analysis has limitations as well (s. Klauke et al. 2010 for a striking example of a mutation in the gene DES).

ACCEPTED MANUSCRIPT Categorization of genetic variants based on the absence of co-segregation alone might be therefore also misleading. In the case of DES-p.L136P three criteria for pathogenicity are fulfilled, which we have discussed in our manuscript: In addition to in vitro functional analysis (strong criterion according to ACMG) this sequence variant is absent in public exome databases (moderate criterion). Moreover, different in silico prediction tools indicate also damaging/pathogenic effects of DES-p.L136P (supportive

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criterion), which is in agreement with the results of our filament assembly experiments. The combination of a strong, moderate and supportive criterion leads according to the ACMG guidelines to the classification ‘Likely pathogenic’ and not 'Pathogenic' as it was assumed by the authors of the letter.

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However, as we have underlined in our manuscript that additional genetic, epigenetic or environmental (co)-factors might contribute to the clinical

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phenotype. We discussed this aspect in the limitation section of our manuscript. Since mechanistic effects of the vast majority of cardiomyopathy associated mutations are still lacking, in vitro evidence - as we presented -

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has its impact for the classification of mutations and are therefore regarded as criteria in the ACMG guidelines. In this context the protein damaging in vitro

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effects of DES-p.L136P cannot be ignored. In contrast to the notion of the authors, we have been well aware that DES-

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p.L136P did not co-segregate within the pedigree and we therefore did not assume that the cousins were carrier of the mutation because we were not

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able to determine the genotype ('unknown genotype'; s. Results) (Brodehl et al. 2016). Our intention was to report especially this discrepancy between in vitro and clinical data! Therefore, Azzimato and colleagues pointed out in the corresponding editorial 'faced with the complexity of genetics the only that can be done is to test the validity of a hypothesis by comparing prediction with experience' (Azzimato et al. 2016).

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