Samenvatting

Secondary cardiac arrhythmias, or cardiomyopathies are characterized by structural abnormalities of the cardiac muscle. These diseases are associated with arrhythmias, heart failure and sudden cardiac death. The cardiomyopathies are a heterogeneous group of diseases mainly comprising of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The prevalence of these diseases ranges from 1/500 in HCM to 1/5000 in ARVD/C and in more than 50% of the cases there is evidence of familial inheritance. The structural arrhythmias are mainly associated with mutations in genes encoding desmosomal, sarcomeric, cytoskeletal and nuclear envelope proteins.

We developed a gene panel comprised of 184 genes associated with secondary cardiac arrhythmias. This gene panel, based on capturing probes, provides us with a flexible solution to perform next generation sequencing-based mutation detection in patients diagnosed with secondary arrhythmias.
For validation purposes 4 controls (2 healthy, in-house control samples, 2 HapMap samples and one patient with known mutations) were sequenced via enriched exome sequencing (Illumina HiSeq) using standard exome probes spiked-in with the cardiomyopathy specific gene panel probes in order to obtain a diagnostics grade coverage of the genes included in the gene panel. In parallel the same samples were sequenced using only the secondary arrhythmia gene panel probes (Illumina MiSeq)..
In a first step the coverage data were analyzed. Out of the 184 genes, covering about 3400 exons, there were only 15 exons that did not reach our cut-off value of 30x complete exonic coverage in both experimental set-ups. For these exons Sanger sequencing based gap filling was developed. In a second step all variants identified in the cardiomyopathy gene panel in both experimental set-ups were compared. In addition, for the 2 in-house control samples and 2 HapMap samples, the identified variants were compared to whole genome sequencing data and HapMap data respectively. There was a complete concordance between the identified variants irrespective of the sequencing and enrichment methods used. All known variants present in the patient sample were also detected in both experiments.
We are currently evaluating this comprehensive gene panel in patients with a known (likely) pathogenic mutation in a core cardiomyopathy gene identified either through single gene analysis or a limited gene panel analysis.

This pilot study will help us on the one hand in the further validation. On the other hand we simultaneously want to evaluate the additional diagnostic yield of this comprehensive cardiomyopathy gene panel as we expect to identify combinations of (likely) pathogenic variants that probably contribute to the complexity of cardiomyopathy development.

Originele taal-2English
TitelBeSHG & NVHG First Joint Meeting "Genetics & Society"
Plaats van productieLeuven
UitgeverijBelgian Society of Human Genetics
Pagina's181-181
Aantal pagina's1
StatusPublished - 4 feb 2016
EvenementBeSHG & NVHG First Joint Meeting "Genetics & Society" - Leuven, Belgium
Duur: 4 feb 20165 feb 2016

Conference

ConferenceBeSHG & NVHG First Joint Meeting "Genetics & Society"
LandBelgium
StadLeuven
Periode4/02/165/02/16

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