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. 2017 Dec 7;38(46):3461-3468.
doi: 10.1093/eurheartj/ehw603.

Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes

Roddy Walsh  1   2 , Rachel Buchan  1   2 , Alicja Wilk  1   2 , Shibu John  1   2 , Leanne E Felkin  1   2 , Kate L Thomson  3   4 , Tang Hak Chiaw  5 , Calvin Chin Woon Loong  5 , Chee Jian Pua  5 , Claire Raphael  6 , Sanjay Prasad  6 , Paul J Barton  1   2 , Birgit Funke  7   8 , Hugh Watkins  4   9 , James S Ware  2   10 , Stuart A Cook  2   5   10   11
Affiliations

Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes

Roddy Walsh et al. Eur Heart J. .

Abstract

Aim: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.

Methods and results: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence.

Conclusion: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.

Keywords: ExAC; HCM genetics; Hypertrophic cardiomyopathy; Mendelian genetics; Rare genetic variation.

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Figures

Figure 1
Figure 1
Proportion of HCM patients referred for clinical genetic testing (at OMGL and LMM) with Pathogenic or Likely Pathogenic variants. The percentage in parentheses refer to the total case excess over the frequency of rare variation in ExAC that is expected to reflect the actual yield for each gene (including variants classified as unknown significance shown in the check-patterned slices). The proportions were calculated according to the number of patients sequenced for each gene (up to 6179) and averaged for the three categories - other sarcomeric (ACTC1, MYL2, MYL3, TPM1), other HCM (CSRP3, FHL1, PLN) and metabolic cardiomyopathies (GLA, LAMP2, PRKAG2). Non-essential splice site variants are not included. Over 99% of pathogenic HCM variants occur in the eight core sarcomeric genes (MYH7, MYBPC3, TNNT2, TPM1, MYL2, MYL3, TNNI3, and ACTC1). HCM, Hypertrophic cardiomyopathy.
Figure 2
Figure 2
Evidence used to classify genes associated with hypertrophic cardiomyopathy. For full details on the criteria for each category, see Supplementary material online, Table S2.
Figure 3
Figure 3
Scatter plot summarizing the evidence for involvement of genes implicated in hypertrophic cardiomyopathy (low frequency genes in main plot, higher frequency genes in subplot). The frequency of rare variants in combined cases is shown on the y-axis and in Exome Aggregation Consortium on the x-axis. Genes with an excess in cases are displayed above the diagonal. Data points are coloured according to classification by this study, shaped according to gene function and sized according to amount of published segregation data.
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