Figure 3
Variant interpretation. (a) Distribution of rare (Exome Aggregation Consortium (ExAC) minor allele frequency <1 × 10−4) MYH7 missense variants in hypertrophic cardiomyopathy (HCM) (n = 864) and dilated cardiomyopathy (DCM) (n = 69) clinical cohorts and ExAC (n = 816), with the key myosin protein regions highlighted. Using nonrandom mutation cluster analysis (NMC), (refer to Supplementary Methods online), a significant variant cluster (P < 3 × 10−15, false discovery rate (FDR), q < 5 × 10−13) was identified between residues 181 and 937 (involving the motor domain, lever arm, and part of the rod) in HCM cases, and depletion in this region and a significant cluster (P < 3 × 10−8, FDR q < 4 × 10−5) was identified between residues 1,271 and 1,903 (in the part of the rod that forms the filament backbone) in ExAC samples. The etiological fraction (EF) for a rare MYH7 missense variant identified in a HCM proband ranges from 0.97 in the HCM cluster to 0.67 in the control cluster. Vertical gray bars depict the positions of variants in cohorts; grayscale shows variant density where variants are coincident. An overview of the genetic landscape of HCM (b) and DCM (c) for truncating (blue) and nontruncating (gray) variants, as well as MYH7 missense variants in the clusters identified in (a) (orange, disease cluster; yellow, ExAC control cluster). The case excess (y-axis) is the frequency of rare variation in disease cohorts over and above the frequency in ExAC and indicates the relative importance of the gene and variant class to the genetic etiology of each cardiomyopathy. The etiological fraction (EF) (x-axis) is an estimate of the proportion of affected carriers where the variant caused the disease; it is a measure of the interpretability of variants of this class (see Supplementary Table S4a,b online for full details). This measure is an average of all variants of a given class; some of which will be pathogenic but others will be benign.
