The role of rare variants in ACTN2 as causative mutations in Dilated Cardiomyopathy is described below. By comparing the frequency of ACTN2 variants in large DCM clinical cohorts to the background population rate in the ExAC database, the proportion of DCM patients with pathogenic mutations in ACTN2 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) ACTN2 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 ACTN2 variants in DCM: -0.19% (p=0.7440)
Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in ACTN2 found in 895 DCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database. As there is no excess burden of variation in the disease cohort, this analysis suggests that ACTN2 variants do not contribute to DCM.
| All Vars | Truncating | Non-Truncating | |
|---|---|---|---|
| Excess in DCM | -0.19% p=0.7440 |
-0.01% p=1.0000 |
-0.18% p=0.7436 |
| Etiological fraction | - | - | - |
| Odds Ratio | 0.82 0.35 - 1.63 |
0.00 0.00 - 43.23 |
0.83 0.36 - 1.65 |
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) | 895 | All | 8 | 0.00894 | 0.01086 | -0.00192 | |
| Truncating | 0 | 0.00000 | 0.00010 | -0.00010 | |||
| Non-Truncating | 8 | 0.00894 | 0.01076 | -0.00182 | |||
| OMGL1 | 305 | All | 3 | 0.00984 | 0.01086 | -0.00102 | |
| Truncating | 0 | 0.00000 | 0.00010 | -0.00010 | |||
| Non-Truncating | 3 | 0.00984 | 0.01076 | -0.00092 | |||
| LMM2 | 590 | All | 5 | 0.00847 | 0.01086 | -0.00239 | |
| Truncating | 0 | 0.00000 | 0.00010 | -0.00010 | |||
| Non-Truncating | 5 | 0.00847 | 0.01076 | -0.00229 | |||
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.
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