DES in Dilated Cardiomyopathy (DCM)

The role of rare variants in DES as causative mutations in Dilated Cardiomyopathy is described below. By comparing the frequency of DES variants in large DCM clinical cohorts to the background population rate in the ExAC database, the proportion of DCM 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 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 DES variants in DCM: 0.42% (p=0.0806)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in DES found in 894 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	0.42% p=0.0806	0.19% p=0.0376	0.24% p=0.2998
Etiological fraction	0.48 0.00 - 0.74	0.86 0.00 - 0.97	0.35 0.00 - 0.71
Odds Ratio	1.91 0.81 - 3.83	7.16 0.80 - 30.53	1.53 0.55 - 3.39

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)	894	All	8	0.00895	0.00472	0.00423
		Truncating	2	0.00224	0.00036	0.00188
		Non-Truncating	6	0.00671	0.00436	0.00235

OMGL1	304	All	3	0.00987	0.00472	0.00515
		Truncating	0	0.00000	0.00036	-0.00036
		Non-Truncating	3	0.00987	0.00436	0.00551

LMM2	590	All	5	0.00847	0.00472	0.00375
		Truncating	2	0.00339	0.00036	0.00303
		Non-Truncating	3	0.00508	0.00436	0.00072

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.