Genetics of Dilated Cardiomyopathy

Study Questions:

What is the utility of high-quality oligonucleotide-selective sequencing (OS-Seq) as a diagnostic tool in dilated cardiomyopathy (DCM), and the genetic profile of DCM in a Finnish population?

Methods:

The study cohort was comprised of 145 unrelated DCM patients (63 familial and 82 sporadic) of Finnish origin recruited between 1999 and 2013 from Helsinki Hospital, the only center to perform cardiac transplantation. The study investigators utilized OS-Seq to target and sequence the coding regions and splice junctions of 101 genes associated with cardiomyopathies in this study cohort. The investigators developed an effective bioinformatic variant filtering strategy and implemented a strict variant classification scheme to reveal diagnostic yield and genotype–phenotype correlations.

Results:

The study investigators found that their implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was high at 35.2% (familial 47.6% and sporadic 25.6%, p = 0.004) when both pathogenic and likely pathogenic variants were considered as disease causing. Disease-causing genes included TTN (17.2%); lamin A/C (LMNA) (8.3%); desmoplakin (DSP) (5.5%); RNA-binding motif protein 20 (RBM20) (1.4%); myosin, heavy chain 7 (MYH7), troponin T type 2 (TNNT2), dystrophin (DMD), and titin-cap (TCAP) (0.7%). Of these, 53% (n = 20) were titin (TTN) truncations (nonsense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively. The sensitivity was 99.0% in HapMap (NA12878) validation, with an accuracy that was significantly better than other reported studies (100.00 vs. 91.3%). Limitations of the study include the fact that the investigators were unable to perform comprehensive co-segregation analysis in many cases due to sporadic DCM, and low number of family member samples in familial cases.

Conclusions:

The study investigators concluded that panel-based, high-quality next-generation sequencing has a high diagnostic yield in the familial form of DCM, and bioinformatic-variant filtering is a dependable tool in the interpretation of genomic data.

Perspective:

The findings of this study are important because it profiles the genetic makeup of DCM in the Finnish population, and more importantly, it validates the utility of the novel OS-Seq technology. The investigators found that this novel technology is a comprehensive diagnostic tool with a high diagnostic yield in their cohort. The next step would be to determine whether this high diagnostic yield will be obtained in other DCM populations. If so, this technology would greatly enhance our understanding of DCM.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Genetic Arrhythmic Conditions, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Heart Transplant

Keywords: Biological Markers, Cardiomyopathy, Dilated, Codon, Nonsense, Computational Biology, Connectin, Desmoplakins, Dystrophin, Genetic Association Studies, HapMap Project, Heart Failure, Heart Transplantation, Lamin Type A, Myosins, Nucleotides, Oligonucleotides, Troponin T


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