MYOZ2 in Hypertrophic Cardiomyopathy (HCM)

Evidence for role of MYOZ2 in HCM

A detailed analysis of the role of non-sarcomeric genes in HCM - incorporating clinical sequencing data from the OMGL and LMM labs, 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 - has clarified the involvement of MYOZ2 variants in this condition (see our study published in the European Heart Journal for further details).

Based on this analysis, MYOZ2 is classified as having: Moderate Evidence


Case excess (gene)Max LOD scoreCase excess (variant)De novo variant
no excess2.0 - -
See details belowp.S48P (PMID:17347475)

Cohort (reference)HCM patients testedRare variantsCase FrequencySignificance vs ExAC
17347475 516 0 0.00000 no excess
18591919 438 0 0.00000 no excess
27532257 632 1 0.00158 no excess
28082330 804 1 0.00124 no excess
Total 2390 2 0.00084 no excess

Summary of the frequency of rare MYOZ2 variants (ExAC frequency < 0.0001) in published cohorts of HCM probands. P-values shown are from Fisher' Exact test compared to rare variants in ExAC (ExAC frequency = 0.00256). Significance is based on multiple testing correction of 31 genes tested (p<0.0016).


Data from clinical cohorts

By comparing the frequency of MYOZ2 variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in MYOZ2 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) MYOZ2 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 MYOZ2 variants in HCM: -0.10% (p=1.0000)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in MYOZ2 found in 632 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database. As there is no excess burden of variation in the disease cohort, this analysis suggests that MYOZ2 variants do not contribute to HCM.


Metrics by Variant Class:
All VarsTruncatingNon-Truncating
Excess in HCM -0.10%
p=1.0000
-0.02%
p=1.0000
-0.08%
p=1.0000
Etiological fraction - - -
Odds Ratio 0.62
0.15 - 3.50
0.00
0.00 - 30.64
0.67
0.02 - 3.80

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.



SourceSamples
Tested
Variant
Type
Variants
detected
Frequency
in HCM
Frequency
in ExAC
Case Excess
in HCM
LMM2632All1 0.001580.00256-0.00098
Truncating00.000000.00020-0.00020
Non-Truncating1 0.001580.00236-0.00078

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.