Atlas of the Clinical Genetics of Human Dilated Cardiomyopathy
What is the role of next-generation sequencing in determining the genetic basis of dilated cardiomyopathy (DCM)?
A total of 639 patients with sporadic or familial DCM were studied with ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold, and a mean read depth of 2,415.
The highest number of known cardiomyopathy mutations were found in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When unknown but predicted disease variants were included, titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants were among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy, and channelopathy causing mutations is considerably high. Greater than 38% of patients have compound or combined mutations, and 12.8% have three or more mutations. When comparing patients recruited in the eight participating European countries, there were minimal differences in mutation frequencies and affected genes.
This is the first study to comprehensively investigate the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. These results underline the high analytical quality and feasibility of next-generation sequencing in clinical genetic diagnostics, and provide a sound database of the genetic causes of DCM.
The rapid improvements in sequencing technology will facilitate the widespread application of genetic testing to diseases such as the cardiomyopathies where multiple disease-causing genes have been previously identified. Although the actual contribution of the specific gene variant toward the phenotype will still need to be proven in individual patients, this study suggests that in many cases (>38%), several combined mutations may contribute to the phenotype, highlighting the genetic complexity of these diseases and possibly accounting for phenotypic heterogeneity between subjects.
Keywords: High-Throughput Nucleotide Sequencing, Cardiomyopathy, Hypertrophic, Genetic Testing, Plakophilins, Connectin, Mutation Rate, Ryanodine Receptor Calcium Release Channel, Myosins, Desmoglein 2, Desmocollins, Desmoplakins, Phenotype, Carrier Proteins, Channelopathies, Cardiomyopathy, Dilated
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