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.

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

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.

Gene	Total cases	HCM frequency	ExAC frequency	Fisher's exact p-value	Max LOD score	de novo	Individual variant excess
Strong Evidence
CSRP3	4866	0.00904	0.00324	p<0.0001	3.6		Y
FHL1	2061	0.00922	0.00123	p<0.0001		Y	Y
PLN	5440	0.00331	0.00048	p<0.0001			Y
Moderate Evidence
ACTN2	2779	0.01116	0.01086	n/s	2.8
CRYAB	804	0.00249	0.00208	n/s		Y
FLNC	92	0.08696	0.03211	p=0.0097	2.3
MYOZ2	2390	0.00084	0.00256	no excess	2.0
Weak Evidence
MYH6	1709	0.03803	0.02466	p=0.001
TNNC1	3335	0.00240	0.00060	p=0.002	1.2
TRIM55	993	0.02014	0.00734	p<0.0001
TRIM63	1398	0.01431	0.00514	p<0.0001
Functional data only (no genetic evidence)
ANKRD1	1995	0.00501	0.00354	n/s
CAV3	1824	0.00055	0.00138	no excess	0.6
FHL2	520	0.00577	0.00310	n/s
FXN	1193	0.00168	0.00132	n/s
JPH2	1292	0.00697	0.00654	n/s
KLF10	1328	0.00678	0.00486	n/s
LDB3	1518	0.00725	0.01122	no excess
MYLK2	1294	0.00773	0.00782	no excess
MYOM1	188	0.00532	0.02394	no excess	0.6
MYPN	1381	0.01521	0.01434	n/s
NEXN	1557	0.01220	0.00756	n/s	0.9
TCAP	2413	0.00290	0.00242	n/s
No Evidence
CALR3	1056	0.00095	0.00456	no excess
CASQ2	1930	0.00518	0.00508	n/s
LMNA	1678	0.00775	0.00624	n/s
OBSCN	0		0.11066	-
PDLIM3	1771	0.00621	0.00506	n/s
SRI	252	0.00000	0.00214	no excess
TRIM54	993	0.01309	0.00510	p=0.002
VCL	2358	0.00891	0.10160	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.

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. 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.