Narrowing Beta-myosin hot spots in its association with hypertrophic cardiomyopathy

Abstract Introduction MYH7 encodes to β-cardiac myosin heavy chain, a large and pleomorphic protein, conformed by different well-functionally characterized domains. This gene has an enormous contribution hypertrophic cardiomyopathy (HCM) but also other cardiomyopathies such as dilated, non-compaction restrictive (and overlapping phenotypes). There are specific adapted recommendations for classifying variants in this regarding its association with HCM; one of the aspects was location head domain, encompassing 181–937 residues moderate ACMG criteria (Kelli et al., 2018). Objectives The purpose analysis determine if more regions MYH7are enriched HCM cases. could help better characterise those where identifying novel missense variant reinforce their pathogenicity. Methods We included 26,929 consecutives unrelated probands which sequenced NGS, referred from countries centres. performed enrichment comparing prevalence rare (pre-established MAF cut-off 0.004%) cases diagnosis versus frequency non-cardiomyopathy (internal controls, OR_int, comprising aortic diseases, channelopathies dyslipidaemias) gnomAD population (external OR_ext). Comparison between groups using Student's t-test; p value <0.05 considered indicate statistical significance. rationale grouping avoid skewed analysis, given high degree observed gene. Results 10,064 8,975 phenotype were used internal controls; 7,890 MYH7-related phenotypes (restrictive, skeletal myopathies) not analysis. Rare (OR_int = 11.15; OR_ext =12.44) pre-established hot spot domain 16.43; 24.53). However, highest odds ratios both external comparison central converter (residues 711–755, OR_int 44.39; 50.27) actin-binding region 647–664, =18.77; 69.32). Conversely, tail (both S2 subfragment light meromyosin region, LMM), had lowest OR Conclusions Previously reported hotspot (head) is significantly cases, some within acting-binding have relatively higher contribution. These results current approach, on hand, show asymmetric domain. fact may impact reassessment classification towards precise approach. Funding Acknowledgement Type funding sources: Private company. Main source(s): Health Code