PKP2 in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The role of rare variants in PKP2 as causative mutations in Arrhythmogenic Right Ventricular Cardiomyopathy is described below. By comparing the frequency of PKP2 variants in large ARVC clinical cohorts to the background population rate in the ExAC database, the proportion of ARVC patients with pathogenic mutations in PKP2 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) PKP2 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 PKP2 variants in ARVC: 26.62% (p<0.0001)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in PKP2 found in 361 ARVC samples sequenced by OMGL and in reference samples of the ExAC population database.

Metrics by Variant Class:

	All Vars	Truncating	Non-Truncating
Excess in ARVC	26.62% p<0.0001	26.24% p<0.0001	0.38% p=0.4767
Etiological fraction	0.96 0.95 - 0.97	1.00 1.00 - 1.00	0.23 0.00 - 0.65
Odds Ratio	28.22 21.96 - 36.04	484.73 326.79 - 724.86	1.30 0.47 - 2.87

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	361	All	101	0.27978	0.01358	0.26620
		Truncating	95	0.26316	0.00076	0.26240
		Non-Truncating	6	0.01662	0.01280	0.00382

References

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.