The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Abstract

PURPOSE:

Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory.

METHODS:

Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses.

RESULTS:

Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%.

CONCLUSION:

Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.

• Authors: Trevor J Pugh, Melissa A Kelly, Sivakumar Gowrisankar, Elizabeth Hynes, Michael A Seidman, Samantha M Baxter, Mark Bowser, Bryan Harrison, Daniel Aaron, Lisa M Mahanta, Neal K Lakdawala, Gregory McDermott, Emily T White, Heidi L Rehm, Matthew Lebo, Birgit H Funke
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 16 Issue 8 Pg. 601-8 (Aug 2014) ISSN: 1530-0366 [Electronic] United States
• PMID: 24503780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Connectin
• DSP protein, human
• Desmoplakins
• TTN protein, human
• VCL protein, human
• myosin-binding protein C
• Vinculin

Topics

• Cardiomyopathy, Dilated (genetics)
• Carrier Proteins (genetics)
• Connectin (genetics)
• Desmoplakins (genetics)
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Male
• Sequence Analysis, DNA (methods)
• Vinculin (genetics)