The role of rare variants in DES as causative mutations in Arrhythmogenic Right Ventricular Cardiomyopathy is described below. By comparing the frequency of DES variants in large ARVC clinical cohorts to the background population rate in the ExAC database, the proportion of ARVC patients with pathogenic mutations in DES can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) DES variant identified in a ARVC patient is disease-causing. Summary data for different variant classes (all protein-altering variants, loss of function truncating variants and non-truncating variants) is highlighted - see the table below for full details of this analysis.
Excess of DES variants in ARVC: 2.75% (p=0.0101)
Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in DES found in 93 ARVC samples sequenced by OMGL and in reference samples of the ExAC population database. Please note as this is based on a small ARVC cohort, the data should be used with caution.
| All Vars | Truncating | Non-Truncating | |
|---|---|---|---|
| Excess in ARVC | 2.75% p=0.0101 |
-0.04% p=1.0000 |
2.79% p=0.0084 |
| Etiological fraction | 0.86 0.29 - 0.95 |
- | 0.87 0.34 - 0.96 |
| Odds Ratio | 7.04 1.41 - 21.46 |
0.00 0.00 - 128.58 |
7.54 1.52 - 23.01 |
The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused ARVC. The Odds Ratio (OR) describes the odds of having a rare variant in the patient cohort to the odds in the ExAC cohort. Fisher's exact test p-values are displayed for case excess, 95% confidence intervals for EFs and ORs.
| Source | Samples Tested | Variant Type | Variants detected | Frequency in ARVC |
Frequency in ExAC | Case Excess in ARVC |
|---|---|---|---|---|---|---|
| OMGL1 | 93 | All | 3 | 0.03226 | 0.00472 | 0.02754 |
| Truncating | 0 | 0.00000 | 0.00036 | -0.00036 | ||
| Non-Truncating | 3 | 0.03226 | 0.00436 | 0.02790 |
1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.