DCM - Dilated Cardiomyopathy

To assess the true contribution of rare variants in DCM-associated genes as causative mutations in Dilated Cardiomyopathy, the frequency of rare variation (population mean allelic frequency < 0.0001) in large DCM clinical cohorts was compared to the background population rate in the ExAC database. Genes with a clear excess burden of variants in the DCM cohort can be regarded as genes definitively associated with DCM.


This analysis was based on a comparison between a large DCM 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 DCM and ExAC frequencies to view the specific variants.


GeneCases
Sequenced
DCM
frequency
ExAC
frequency
Case Excess in DCMFisher's exact p-value
TTN * 460 0.14565 0.00876 0.13689<0.0001
DSP 427 0.07494 0.03148 0.04346<0.0001
MYH7 1315 0.05323 0.01398 0.03925<0.0001
LMNA 1044 0.04406 0.00622 0.03784<0.0001
TNNT2 1254 0.02871 0.00242 0.02629<0.0001
TPM1 1111 0.01890 0.00086 0.01804<0.0001
VCL 590 0.02203 0.01016 0.011870.0111
TCAP 590 0.01186 0.00242 0.009440.0008
LDB3 740 0.01892 0.01122 0.007700.0544
MYBPC3 1161 0.02498 0.01970 0.005280.2002
ABCC9 590 0.01356 0.00874 0.004820.1847
DES 894 0.00895 0.00472 0.004230.0806
TNNI3 1239 0.00646 0.00228 0.004180.0098
ACTC1 1103 0.00453 0.00064 0.003890.0011
SGCD 590 0.00678 0.00338 0.003400.1437
PLN 1095 0.00365 0.00048 0.003170.0027
TAZ 740 0.00405 0.00094 0.003110.0360
PKP2 427 0.01639 0.01358 0.002810.5287
CRYAB 425 0.00471 0.00208 0.002630.2263
LAMP2 532 0.00376 0.00198 0.001780.2383
CTF1 590 0.00169 0.00046 0.001230.2456
CSRP3 945 0.00423 0.00324 0.000990.5559
MYL2 543 0.00184 0.00176 0.000080.5724
EMD 590 0.00169 0.00166 0.000030.6265
TMEM43 427 0.00703 0.00730 -0.000271.0000
FHL2 425 0.00235 0.00310 -0.000751.0000
SCN5A 304 0.02303 0.02380 -0.000771.0000
GLA 541 0.00000 0.00100 -0.001001.0000
FHL1 355 0.00000 0.00123 -0.001231.0000
PRKAG2 546 0.00366 0.00532 -0.001661.0000
MYL3 543 0.00000 0.00182 -0.001821.0000
ACTN2 895 0.00894 0.01086 -0.001920.7440
ANKRD1 426 0.00000 0.00354 -0.003540.4121
DSC2 427 0.00468 0.00964 -0.004960.4509
DSG2 427 0.00703 0.01298 -0.005950.3877
JUP 425 0.00471 0.01196 -0.007250.2557
For the genes in italics below, the data should be viewed with caution due to the small number (<200) of patients sequenced.
RBM20 156 0.05769 0.01414 0.043550.0005
LAMA4 121 0.04959 0.02282 0.026770.0638
NEXN 156 0.03205 0.00756 0.024490.0071
TNNC1 156 0.01923 0.00060 0.018630.0001
RYR2 121 0.04959 0.03484 0.014750.3284
CASQ2 121 0.01653 0.00508 0.011450.1269
MYLK2 121 0.01653 0.00782 0.008710.2514
DTNA 121 0.00826 0.00436 0.003900.4172
MYH6 121 0.02479 0.02466 0.000131.0000
CAV3 121 0.00000 0.00138 -0.001381.0000
TTR 121 0.00000 0.00140 -0.001401.0000
MYOZ2 121 0.00000 0.00256 -0.002561.0000

* Data for TTN refers to truncating variants only.


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.