MYH7 in Dilated Cardiomyopathy (DCM)

The role of rare variants in MYH7 as causative mutations in Dilated Cardiomyopathy is described below. By comparing the frequency of MYH7 variants in large DCM clinical cohorts to the background population rate in the ExAC database, the proportion of DCM patients with pathogenic mutations in MYH7 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) MYH7 variant identified in a DCM 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 MYH7 variants in DCM: 3.93% (p<0.0001)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in MYH7 found in 1315 DCM 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 DCM	3.93% p<0.0001	0.03% p=0.4756	3.90% p<0.0001
Etiological fraction	0.75 0.67 - 0.80	0.37 0.00 - 0.90	0.75 0.68 - 0.81
Odds Ratio	3.97 3.04 - 5.10	1.59 0.04 - 9.58	4.05 3.10 - 5.22

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused DCM. 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 DCM	Frequency in ExAC	Case Excess in DCM
Combined (OMGL1 + LMM2)	1315	All	70	0.05323	0.01398	0.03925
		Truncating	1	0.00076	0.00048	0.00028
		Non-Truncating	69	0.05247	0.01350	0.03897

OMGL1	559	All	25	0.04472	0.01398	0.03074
		Truncating	0	0.00000	0.00048	-0.00048
		Non-Truncating	25	0.04472	0.01350	0.03122

LMM2	756	All	45	0.05952	0.01398	0.04554
		Truncating	1	0.00132	0.00048	0.00084
		Non-Truncating	44	0.05820	0.01350	0.04470

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. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.