Narrowing Beta-myosin hot spots in its association with hypertrophic cardiomyopathy
Authors: Garcia Hernandez S , De La Higuera Romero L , Fernandez X , Valverde Gomez M , Cazon Varela L , Peteiro Deben R , Rebolo P , Sanluis Verdes A , Cardenas I , Ortiz-Genga M , Amor Salamanca A , Perez Barbeito M , Gomez Diaz I , Sanchez Flores M , Ochoa J P 
Published: October 2022

Abstract

Introduction
MYH7 encodes to β-cardiac myosin heavy chain, a large and pleomorphic protein, conformed by different and well-functionally characterized domains. This gene has an enormous contribution to hypertrophic cardiomyopathy (HCM) but also to other cardiomyopathies such as dilated, non-compaction and restrictive cardiomyopathy (and overlapping phenotypes). There are specific and adapted recommendations for classifying variants in this gene regarding its association with HCM; one of the aspects was the location of variants in the head domain, encompassing 181–937 residues as moderate ACMG criteria (Kelli et al., 2018).

Objectives
The purpose of this analysis was to determine if more specific regions of MYH7are enriched in HCM cases. This analysis could help to better characterise those regions where identifying a novel missense variant could reinforce their pathogenicity.

Methods
We included in the analysis 26,929 consecutives unrelated probands in which MYH7 was sequenced by NGS, referred from different countries and centres. We performed an enrichment analysis comparing the prevalence of rare missense variants (pre-established MAF cut-off 0.004%) in cases with the diagnosis of HCM versus their frequency in non-cardiomyopathy cases (internal controls, OR_int, comprising aortic diseases, channelopathies and dyslipidaemias) and in gnomAD population (external controls, OR_ext). Comparison between groups was performed using the Student's t-test; p value &lt;0.05 was considered to indicate statistical significance. The rationale of this grouping was to avoid skewed analysis, given the high degree of overlapping cardiomyopathies observed in this gene.

Results
HCM was the diagnosis in 10,064 cases. 8,975 probands with a non-cardiomyopathy phenotype were used as internal controls; 7,890 cases with other MYH7-related phenotypes (restrictive, dilated, non-compaction and skeletal myopathies) were not included in the analysis. Rare missense variants in MYH7 were enriched in HCM cases (OR_int = 11.15; OR_ext =12.44) and in the pre-established hot spot head domain (OR_int = 16.43; OR_ext = 24.53). However, the regions with the highest odds ratios in both external and internal comparison were the central converter domain (residues 711–755, OR_int = 44.39; OR_ext = 50.27) and actin-binding region (residues 647–664, OR_int =18.77; OR_ext = 69.32). Conversely, the tail region (both S2 subfragment and light meromyosin region, LMM), had the lowest OR in this analysis.

Conclusions
Previously reported hotspot (head) is significantly enriched in HCM cases, but some specific regions within this domain, such as central converter and acting-binding region, could have a relatively higher contribution. These results reinforce the current approach, but on the other hand, show an asymmetric contribution within the head domain. This fact may have an impact on the reassessment of the variant classification in this gene towards a more precise approach.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Health in Code