HCM - Hypertrophic Cardiomyopathy

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.

Case Excess in HCMFisher'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 0.005250.0001
NEXN 632 0.01266 0.00756 0.005100.1584
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 0.002750.0002
CSRP3 2167 0.00508 0.00324 0.001840.1766
TTR 632 0.00316 0.00140 0.001760.2264
ANKRD1 807 0.00496 0.00354 0.001420.5409
TNNC1 632 0.00000 0.00060 -0.000601.0000
MYOZ2 632 0.00158 0.00256 -0.000981.0000
ACTN2 1439 0.00695 0.01086 -0.003910.1942

Role of non-sarcomeric genes in HCM

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.

GeneTotal casesHCM
Fisher's exact
de novoIndividual
Strong Evidence
CSRP3 48660.009040.00324 p<0.00013.6Y
FHL1 20610.009220.00123 p<0.0001YY
PLN 54400.003310.00048 p<0.0001Y
Moderate Evidence
ACTN2 27790.011160.01086 n/s2.8
CRYAB 8040.002490.00208 n/sY
FLNC 920.086960.03211 p=0.00972.3
MYOZ2 23900.000840.00256 no excess2.0
Weak Evidence
MYH6 17090.038030.02466 p=0.001
TNNC1 33350.002400.00060 p=0.0021.2
TRIM55 9930.020140.00734 p<0.0001
TRIM63 13980.014310.00514 p<0.0001
Functional data only (no genetic evidence)
ANKRD1 19950.005010.00354 n/s
CAV3 18240.000550.00138 no excess0.6
FHL2 5200.005770.00310 n/s
FXN 11930.001680.00132 n/s
JPH2 12920.006970.00654 n/s
KLF10 13280.006780.00486 n/s
LDB3 15180.007250.01122 no excess
MYLK2 12940.007730.00782 no excess
MYOM1 1880.005320.02394 no excess0.6
MYPN 13810.015210.01434 n/s
NEXN 15570.012200.00756 n/s0.9
TCAP 24130.002900.00242 n/s
No Evidence
CALR3 10560.000950.00456 no excess
CASQ2 19300.005180.00508 n/s
LMNA 16780.007750.00624 n/s
OBSCN 00.11066 -
PDLIM3 17710.006210.00506 n/s
SRI 2520.000000.00214 no excess
TRIM54 9930.013090.00510 p=0.002
VCL 23580.008910.10160 no 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.