Acquirement of Clinical and Genomic Data to Diagnose in Rare Inherited Cardiomyopathy
Background Information Cardiomyopathy is one of the leading causes of heart failure. In cases where cardiomyopathy does not respond to guideline-directed medical therapy for heart failure, the disease may progress to a stage where heart transplantation is the only viable treatment option. According to the 2022 Korean Organ Transplant Registry (KOTRY) report, cardiomyopathy accounted for approximately 65% of heart transplant indications in Korea, making it one of the most challenging unresolved issues in modern cardiology. Furthermore, cardiomyopathy is associated with a high risk of sudden cardiac death due to ventricular fibrillation or ventricular tachycardi and implantable cardioverter-defibrillators are often recommended as a preventive measure. Given that sudden cardiac death frequently occurs in young and middle-aged individuals, it is a major public health concern in developed countries such as North America and Western/Northern Europe, prompting ongoing societal and medical efforts to reduce its burden. The risk of sudden cardiac death imposes a persistent psychological burden on family members of patients with cardiomyopathy. Because sudden death can also occur in children and adolescents, current clinical guidelines recommend early cardiac evaluation and genetic counseling for family members of affected individuals. This study seeks to overcome the current limitations in the genetic diagnosis of cardiomyopathy, including the low diagnostic yield of currently available gene panels. To date, most genetic data on cardiomyopathy have been derived from Western populations. There is a significant lack of population-specific genomic data for East Asians, particularly Koreans, making it difficult to interpret the results of genetic testing in Korean patients. By developing bioinformatics algorithms that comprehensively analyze whole genome sequencing (WGS) data, including single nucleotide variants (SNVs), insertions/deletions (indels), and structural variations, this study aims to generate a reference dataset tailored to the Korean population. This will directly improve the genetic diagnosis of cardiomyopathy in Korean patients. Additionally, by identifying novel pathogenic variants through WGS, this study may elucidate new disease mechanisms underlying cardiomyopathy. These findings could provide a theoretical basis for developing novel diagnostic biomarkers, therapeutic targets, and even gene-based therapies. The present study is part of a multi-phase national research project supported by the Korea Disease Control and Prevention Agency and the Korea National Institute of Health, conducted as a registry cohort titled the Korean Cardiomyopathy Cohort (KCC). Objectives This study aims to establish a diagnostic research framework to elucidate the genetic architecture of rare inherited cardiomyopathies through comprehensive analysis of whole genome sequencing data, with the goal of identifying novel diagnostic approaches
⁃ patients aged 19 years or older who have provided written consent for participation, have the capability to consent voluntarily and have been diagnosed with cardiomyopathy, as defined by one of the following criteria: -Ones with suspected genetic cardiomyopathy of unknown etiology, meeting at least one of the following conditions: i) Patients with idiopathic cardiomyopathy, for whom no clear secondary causes (e.g., history of hypertension, alcohol abuse, or chemotherapy) can be identified, and in whom a genetic etiology is strongly suspected.
⁃ ii) Patients who have previously undergone genetic testing using an NGS panel, but no pathogenic variants were identified, and further evaluation with whole genome sequencing (WGS) is warranted.
⁃ iii) Patients diagnosed with cardiomyopathy before the age of 50, without known contributing factors such as hypertension or excessive alcohol consumption, raising a strong suspicion of a genetic cause.
• Patients with a family history of genetic cardiomyopathy, defined as having at least one first-degree relative (parent, sibling, or child) diagnosed with the same type of cardiomyopathy, confirming a familial genetic pattern.