Abstract
BackgroundRapidly determining the complex genetic basis of Hypertrophic cardiomyopathy (HCM) is vital to better understanding and optimally managing this common polygenetic cardiovascular disease.MethodsA rapid custom Ion-amplicon-resequencing assay, covering 30 commonly affected genes of HCM, was developed and validated in 120 unrelated patients with HCM to facilitate genetic diagnosis of this disease. With this HCM-specific panel and only 20 ng of input genomic DNA, physicians can, for the first time, go from blood samples to variants within a single day.ResultsOn average, this approach gained 595628 mapped reads per sample, 95.51% reads on target (64.06 kb), 490-fold base coverage depth and 93.24% uniformity of base coverage in CDS regions of the 30 HCM genes. After validation, we detected underlying pathogenic variants in 87% (104 of 120) samples. Tested seven randomly selected HCM genes in eight samples by Sanger sequencing, the sensitivity and false-positive-rate of this HCM panel was 100% and 5%, respectively.ConclusionsThis Ion amplicon HCM resequencing assay provides a currently most rapid, comprehensive, cost-effective and reliable measure for genetic diagnosis of HCM in routinely obtained samples.
Highlights
Determining the complex genetic basis of Hypertrophic cardiomyopathy (HCM) is vital to better understanding and optimally managing this common polygenetic cardiovascular disease
On average, this approach gained 595628 mapped reads per sample, 95.51% reads on target (64.06 kb), 490-fold base coverage depth and 93.24% uniformity of base coverage in CDS regions of the 30 HCM genes
Disease-causing mutations in MYH7, MYBPC3 and TNNT2 had been considered to explain about half of HCM patients [8,9], the frequency of each causal variant is relatively low and most rare mutations are unique in specific families [13]
Summary
Determining the complex genetic basis of Hypertrophic cardiomyopathy (HCM) is vital to better understanding and optimally managing this common polygenetic cardiovascular disease. Hypertrophic cardiomyopathy (HCM) is regarded as a most common inherited cardiac disorder (1/500) and the leading cause of sudden cardiac death in adolescents [1,2,3,4]. Over 1000 mutations in at least 30 genes have been reported to responsible for HCM, which implied an highly genetic heterogeneity and resulting various clinical phenotypes, ranging from asymptomatic forms to sudden cardiac death in the young [3,5,6,7,8,9,10,11,12]. Systemic genetic diagnosis for HCM patients was necessary and recommended by current clinical guidelines [14,15,16,17].
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