The role of rare variants in PLN as causative mutations in Hypertrophic Cardiomyopathy is described below. By comparing the frequency of PLN variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in PLN can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) PLN 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 PLN variants in HCM: 0.28% (p=0.0002)
Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in PLN found in 2167 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database.
| All Vars | Truncating | Non-Truncating | |
|---|---|---|---|
| Excess in HCM | 0.28% p=0.0002 |
0.18% p=0.0001 |
0.10% p=0.0713 |
| Etiological fraction | 0.85 0.60 - 0.94 |
0.96 0.81 - 0.99 |
0.70 0.00 - 0.91 |
| Odds Ratio | 6.75 2.49 - 15.78 |
27.96 5.20 - 150.17 |
3.35 0.65 - 11.00 |
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) | 2167 | All | 7 | 0.00323 | 0.00048 | 0.00275 | |
| Truncating | 4 | 0.00185 | 0.00006 | 0.00179 | |||
| Non-Truncating | 3 | 0.00138 | 0.00042 | 0.00096 | |||
| OMGL1 | 1535 | All | 5 | 0.00326 | 0.00048 | 0.00278 | |
| Truncating | 3 | 0.00195 | 0.00006 | 0.00189 | |||
| Non-Truncating | 2 | 0.00130 | 0.00042 | 0.00088 | |||
| LMM2 | 632 | All | 2 | 0.00316 | 0.00048 | 0.00268 | |
| Truncating | 1 | 0.00158 | 0.00006 | 0.00152 | |||
| Non-Truncating | 1 | 0.00158 | 0.00042 | 0.00116 | |||
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.