To assess the true contribution of rare variants in ARVC-associated genes as causative mutations in Arrhythmogenic Right Ventricular Cardiomyopathy, the frequency of rare variation (population mean allelic frequency < 0.0001) in large ARVC clinical cohorts was compared to the background population rate in the ExAC database. Genes with a clear excess burden of variants in the ARVC cohort can be regarded as genes definitively associated with ARVC.
This analysis was based on a comparison between a large ARVC cohort sequenced at OMGL1 laboratories and rare variants (MAF < 0.0001) in the ExAC population database. The case excess observed is equivalent to the proportion of patients with pathogenic mutations in each gene (Fisher's exact p-value in bold indicates a significant excess, corrected for multiple testing). Click on the gene names for more details, including a breakdown by variant class and Odds Ratios / Etiological Fractions for truncating and non-truncating variants, or click on the ARVC and ExAC frequencies to view the specific variants.
| Gene | Cases Sequenced | ARVC frequency | ExAC frequency |
Case Excess in ARVC | Fisher's exact p-value | |
|---|---|---|---|---|---|---|
| PKP2 | 361 | 0.27978 | 0.01358 | 0.26620 | <0.0001 | |
| DSP | 352 | 0.12216 | 0.03148 | 0.09068 | <0.0001 | |
| DSG2 | 354 | 0.04802 | 0.01298 | 0.03504 | <0.0001 | |
| DSC2 | 351 | 0.02564 | 0.00964 | 0.01600 | 0.0080 | |
| For the genes in italics below, the data should be viewed with caution due to the small number (<200) of patients sequenced. | ||||||
| JUP | 94 | 0.08511 | 0.01196 | 0.07315 | <0.0001 | |
| DES | 93 | 0.03226 | 0.00472 | 0.02754 | 0.0101 | |
| LMNA | 93 | 0.00000 | 0.00622 | -0.00622 | 1.0000 | |
| TMEM43 | 94 | 0.00000 | 0.00730 | -0.00730 | 1.0000 | |
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.