The Dawn of Precision Medicine in Cardiomyopathies ― Advance Preparations of Ethnicity-Specific Database ―
論文ID: CJ-21-0424
この記事には本公開記事があります。
詳細
論文ID: CJ-21-0424
The concept of ‘precision medicine’, announced by President Barack Obama in January 2015, has spread widely. Precision medicine aims to create specialized treatment regimens that are tailored to each individual’s unique genetics, environment and lifestyle. Because idiopathic cardiomyopathies are genetic diseases, patients’ genetic information should be essential for the realization of precision medicine for both patients and their relatives in families with idiopathic cardiomyopathy. Today, acquisition of genetic information for cardiomyopathies is stagnating. Particularly for dilated cardiomyopathy (DCM), identification of disease-causing variants seems hard to accomplish because of the diversity of known causative genes.1 With advances in genetic testing methods, however, multiple genes, including TTN encoding titin, a giant protein consisting of 35,991 amino acids, can be analyzed simultaneously. Thus, the situation is changing for the better. The interpretation of genetic testing results followed by accurate identification of clinically significant variants remains to be a major challenge in cardiovascular genetics.
Article p ????
In this issue of the Journal, Nguyen et al2 provide an overview of Vietnamese DCM patients’ genetic profiles, which can be regarded as valuable evidence from an Asian population. They analyzed 58 DCM-related genes in 230 well-phenotyped DCM patients and found that the diagnostic yield was 23.5% (44.0% in familial cases and 19.6% in sporadic cases) and TTN-truncating variants (TTNtv) accounted for 48% of all genotype-positive DCM patients. They also evaluated the genotype-phenotype correlations, comparing genotype-positive and genotype-negative patients, TTNtv-positive and genotype-negative patients, and TTNtv-positive patients and those with mutations in genes other than TTN. As with previous reports,3,4 genotype-positive patients had composite outcomes (death from any cause, heart transplantation, non-fatal stroke, life-threatening arrhythmia requiring implantable cardioverter defibrillator (ICD) implantation) more frequently and at a younger age than genotype-negative ones. On the other hand, TTNtv-positive patients showed a higher survival rate than those with mutations in other genes, despite unfavorable clinical characteristics that include male sex, family history of DCM, increased left atrial volume index, and younger age at diagnosis. The better therapeutic response in Vietnamese DCM patients with TTNtv is consistent with Japanese data reported by Tobita et al; most Japanese patients harboring TTNtv achieved left ventricular reverse remodeling with optimal therapy.5
Furthermore, regarding genetic evaluation of patients with peripartum cardiomyopathy, alcoholic cardiomyopathy or cancer therapy-induced cardiomyopathy, TTNtv has been identified more frequently as compared with the general population, and patients with TTNtv present more severe clinical characteristics compared with genotype-negative patients.6–8 Given that, TTNtv-positive status could induce DCM-like cardiomyopathies, accompanied by environmental factors such as pregnancy, excess alcohol consumption, and cancer therapy. In other words, TTNtv-positive status is a “bottom-raising factor” for any myocardial abnormality, and it might be possible that the actual onset of cardiomyopathy is triggered by the addition of each environmental factor. In these cases, genetic testing prior to exposure to environmental factors should facilitate strategies to mitigate the disease risk.
Developments in genomic-based precision medicine will propel the opportunities for accurate diagnosis as well as deciding on optimal timing and type of therapeutic intervention. For example, identification of lamin A/C gene (LMNA) variants is considered to be an effective basis for judging early ICD implantation.9 However, the biggest urgent problem to be solved is the interpretation of genetic testing results; that is, determining the pathogenicity grade of sequence variants. Rare variants detected in cardiomyopathy patients cannot be necessarily regarded as pathogenic. Indeed, TTNtv can be detected in 3% of control subjects without cardiomyopathy.10 At present, the pathogenicity of rare variants is not clearly determined by the alternative of true or false, and they are assigned to 1 of 5 grades raging from benign to pathogenic (Figure). In 2015, the American College of Medical Genetic and Genomics (ACMG) and the Association for Molecular Pathology published a standardized tiered system for classification of sequence variants on a spectrum from benign to pathogenic.11 Among them, the variants that meet the criteria for being pathogenic or likely pathogenic are clinically actionable and can be used to guide management decisions or for predictive testing of clinically unaffected relatives in families. Pathogenicity is based on the following: co-segregation in the family, gene function, type of gene variants (e.g., missense, nonsense, frameshift, copy number variation), frequency of variants within the disease group and the general population, and variant function (functional analysis, including in silico data). Notably, we need to confirm these contents even for sequence variants previously reported as “pathogenic”. This variant classification is dynamic and may change over time with expansion of the knowledge base for variant function and disease associations. In order to determine the variant classification appropriately, we need advance preparation of ethnicity-specific databases of previously reported pathogenic/likely-pathogenic variants and variants of uncertain significance, which should be periodically renewed and revised. In addition, it is important to record the clinical phenotypes and outcomes in detail, together with the genetic testing results, which will clarify the genotype-phenotype correlation, improving the genetic diagnosis as well as the prediction of prognosis in genetically affected family members.
Evaluation of pathogenicity of sequence variants identified in genetic testing. VUS, variant of uncertain significance.
H.M. is a member of Circulation Journal’s Editorial Team.
None declared.
