PRKAG2 in Hypertrophic Cardiomyopathy (HCM)

The role of rare variants in PRKAG2 as causative mutations in Hypertrophic Cardiomyopathy is described below. By comparing the frequency of PRKAG2 variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in PRKAG2 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) PRKAG2 variant identified in a HCM 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 PRKAG2 variants in HCM: 0.53% (p=0.0001)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in PRKAG2 found in 3973 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database.

Metrics by Variant Class:

	All Vars	Truncating	Non-Truncating
Excess in HCM	0.53% p=0.0001	0.04% p=0.1103	0.49% p=0.0002
Etiological fraction	0.50 0.29 - 0.64	0.76 0.00 - 0.95	0.49 0.26 - 0.63
Odds Ratio	2.00 1.41 - 2.77	4.15 0.42 - 21.83	1.95 1.36 - 2.72

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused HCM. 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 HCM	Frequency in ExAC	Case Excess in HCM
Combined (OMGL1 + LMM2)	3973	All	42	0.01057	0.00532	0.00525
		Truncating	2	0.00050	0.00012	0.00038
		Non-Truncating	40	0.01007	0.00520	0.00487

OMGL1	1535	All	19	0.01238	0.00532	0.00706
		Truncating	0	0.00000	0.00012	-0.00012
		Non-Truncating	19	0.01238	0.00520	0.00718

LMM2	2438	All	23	0.00943	0.00532	0.00411
		Truncating	2	0.00082	0.00012	0.00070
		Non-Truncating	21	0.00861	0.00520	0.00341

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.

2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.