To assess the true contribution of rare variants in HCM-associated genes as causative mutations in Hypertrophic Cardiomyopathy, the frequency of rare variation (population mean allelic frequency < 0.0001) in large HCM clinical cohorts was compared to the background population rate in the ExAC database. Genes with a clear excess burden of variants in the HCM cohort can be regarded as genes definitively associated with HCM.
This analysis was based on a comparison between a large HCM cohort sequenced at OMGL1 and LMM2 laboratories and rare variants (MAF < 0.0001) in the ExAC population database. The case excess observed is equivalent to the proportion of patients with pathogenic mutations in each gene (Fisher's exact p-value in bold indicates a significant excess, corrected for multiple testing). Click on the gene names for more details, including a breakdown by variant class and Odds Ratios / Etiological Fractions for truncating and non-truncating variants, or click on the HCM and ExAC frequencies to view the specific variants.
| Gene | Cases Sequenced | HCM frequency | ExAC frequency |
Case Excess in HCM | Fisher's exact p-value |
|---|---|---|---|---|---|
| MYBPC3 | 6179 | 0.19032 | 0.01970 | 0.17062 | <0.0001 |
| MYH7 | 6112 | 0.14218 | 0.01398 | 0.12820 | <0.0001 |
| TNNI3 | 6047 | 0.02233 | 0.00228 | 0.02005 | <0.0001 |
| TNNT2 | 6103 | 0.01950 | 0.00242 | 0.01708 | <0.0001 |
| TPM1 | 4447 | 0.01484 | 0.00086 | 0.01398 | <0.0001 |
| MYL2 | 4185 | 0.01099 | 0.00176 | 0.00923 | <0.0001 |
| FHL1 | 1535 | 0.00912 | 0.00123 | 0.00789 | <0.0001 |
| MYL3 | 4185 | 0.00884 | 0.00182 | 0.00702 | <0.0001 |
| GLA | 3700 | 0.00730 | 0.00100 | 0.00630 | <0.0001 |
| PRKAG2 | 3973 | 0.01057 | 0.00532 | 0.00525 | 0.0001 |
| NEXN | 632 | 0.01266 | 0.00756 | 0.00510 | 0.1584 |
| ACTC1 | 4185 | 0.00526 | 0.00064 | 0.00462 | <0.0001 |
| LAMP2 | 3290 | 0.00638 | 0.00198 | 0.00440 | <0.0001 |
| PLN | 2167 | 0.00323 | 0.00048 | 0.00275 | 0.0002 |
| CSRP3 | 2167 | 0.00508 | 0.00324 | 0.00184 | 0.1766 |
| TTR | 632 | 0.00316 | 0.00140 | 0.00176 | 0.2264 |
| ANKRD1 | 807 | 0.00496 | 0.00354 | 0.00142 | 0.5409 |
| TNNC1 | 632 | 0.00000 | 0.00060 | -0.00060 | 1.0000 |
| MYOZ2 | 632 | 0.00158 | 0.00256 | -0.00098 | 1.0000 |
| ACTN2 | 1439 | 0.00695 | 0.01086 | -0.00391 | 0.1942 |
We have expanded our analysis of the role of non-sarcomeric genes in HCM. By utilising the clinical HCM data described above,
a cohort of over 800 HCM probands from the Royal Brompton Hospital, London and the National Heart Centre, Singapore (sequenced
on a broad cardiac NGS panel) and published sequencing, segregation and functional data, we have classified the non-sarcomeric
genes that have been implicated in HCM into the categories shown in the table below. For more details, click on the gene names.
See our study published in the
European Heart Journal3 for further information on this analysis.
| Gene | Total cases | HCM frequency | ExAC frequency |
Fisher's exact p-value | Max LOD score | de novo | Individual variant excess |
|---|
The cases are combined data from the clinical HCM cohorts described above, our prospective HCM cohort (London and Singapore) and published studies. Significance was defined as a p-value of less than 0.0016 (corrected for multiple testing). Maximum LOD scores and de novo variants are from published reports. Individual variant excess refers to single variants which are signficantly enriched in the combined case cohort compared to ExAC. For more details on the classification criteria used, please see our paper in the European Heart Journal.
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.
3. Roddy Walsh, Rachel Buchan, Alicja Wilk, Shibu John, Leanne E. Felkin, Kate L. Thomson, Tang Hak Chiaw, Calvin Chin Woon Loong, Chee Jian Pua, Claire Raphael, Sanjay Prasad, Paul J. Barton, Birgit Funke, Hugh Watkins, James S. Ware, Stuart A. Cook. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J. 2017 doi:10.1093/eurheartj/ehw603.