Letters to the Editor
Identification of Pathogenic Mutations for Dilated Cardiomyopathy Accompanied With Unicuspid Aortic Valve ― Reply ―
2018 Volume 82 Issue 6 Pages 1724-
Details
2018 Volume 82 Issue 6 Pages 1724-
We appreciate Dr. Morita’s and Dr. Komuro’s interest in our study.1 We concur with their comments. As stated by Dr. Morita, family history information is mandatory when caring for patients with dilated cardiomyopathy, whether familial or not. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology suggest that increasing amounts of cosegregation evidence could lead to an evidence criterion of supporting, moderate, or strong evidence that a variant is pathogenic. Non-segregation is considered strong evidence that the variant is benign.2 In the present case, the patient had healthy parents and a young sister with no history of heart disease. Their genetic tests were not performed. In addition, he was single and had no children. Therefore, we did not confirm cosegregation.
In the next-generation sequencing era, genetic screening will help to obtain accurate diagnosis of numerous diseases more efficiently. This advanced technology has the potential to uncover pathogenic mutations and find new disease-causing pathogenic variants. In this sense, we suggested that genetic screening “might” explain the eccentric hypertrophy in the proband and added that “further molecular and functional studies are needed to clarify whether these rare variants are pathogenic”. The CRISPR (clustered, regularly interspaced, short palindromic repeats)/CRISPR-associated 9 (Cas9) system is emerging as a promising genome-editing tool to manipulate genes and analyze functional characterization in various cellular and animal models. We are now planning to manipulate these mutations in zebrafish to define the pathological mechanisms.
As Dr. Morita also mentioned, the relationship between the 2 novel rare variants identified in the present case and clinical presentation with eccentric hypertrophy remains uncertain. Classification of the pathogenicity of variants will be an ongoing and important task. We have to carefully assess whether the rare variants detected in sequencing studies are truly significant regarding the disease. When novel rare variants are identified through genetic screening, close attention should be paid to the interpretation, especially with newly identified rare variants. We again thank Dr. Morita and Dr. Komuro for their valuable comments on our paper.
