![]() ![]() 4, 5 However, the DCM study was limited by the use of patients referred for genetic testing, which introduces important bias (as testing is particularly recommended for young and familial patients, and for clinical subphenotypes with specific genetic associations, such as LMNA cardiomyopathy), by the limited number of cases with data for some genes (range, 121–1315 individuals per gene), and by the absence of data for recently implicated genes such as ZBTB17 6 and BAG3. ![]() We recently demonstrated the potential of this approach through analysis of genes implicated in DCM 4 and hypertrophic cardiomyopathy. The release of the Exome Aggregation Consortium (ExAC) database showed rare variants to be collectively common in the population-with each individual carrying ~54 variants previously reported as pathogenic 3-and provides the opportunity to reappraise putative genetic associations by comparing variant prevalence in patient cohorts with the >60 000 individuals in ExAC. However, previous studies often did not adequately control for background population variation, especially before large reference population datasets were available. 2 Variant interpretation in these genes is a key challenge faced by clinicians and geneticists. The Human Gene Mutation Database collated 68 genes as associated with primary DCM between 19, and >100 genes are now routinely tested in clinical diagnostic laboratories, including those implicated in syndromic forms. 1 The advent of efficient high-throughput sequencing platforms has led to a rapid increase in the number of genes in which variants have been reported as causative, largely based on candidate-gene approaches. By restricting analysis to validated and interpretable genes and variant classes, we can increase the accuracy and reduce the uncertainty associated with clinical genetic testing in DCM.ĭilated cardiomyopathy (DCM) is an inheritable heart disease affecting up to 1 in 250 individuals and is characterized by genetic heterogeneity, and variable penetrance and expressivity.
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