A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank

Abstract

‘Genome-first’ approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into ‘gene burdens’ for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these ‘positive control’ genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

Myh7 regulates SDRC protein and biofilm formation to alleviate osteomyelitis induced by Staphylococcus aureus

“…It was first reported by Geisterfer Lowrance et al in 1990. The MYH7 gene, as the first pathogenic gene found to be associated with hypertrophic cardiomyopathy, has been extensively reported in studies such as myocardial injury [36] . In China, the MYH7 gene mutation range is relatively widespread in patients with hypertrophic cardiomyopathy, except for E6, E7, E10, E17, E24, E25, E29 Pathogenic mutations are present in all 27 exons except for E32 and E33, with 7 mutation sites located in E22 [36,37] .…”

“…The MYH7 gene, as the first pathogenic gene found to be associated with hypertrophic cardiomyopathy, has been extensively reported in studies such as myocardial injury [36] . In China, the MYH7 gene mutation range is relatively widespread in patients with hypertrophic cardiomyopathy, except for E6, E7, E10, E17, E24, E25, E29 Pathogenic mutations are present in all 27 exons except for E32 and E33, with 7 mutation sites located in E22 [36,37] . At the same time, it has been found in Western populations that the most common malignant mutations in patients with myocardial hypertrophy are associated with R403Q, R453C, R719W, and R723G mutations in the MYH7 gene [38,39] .…”

Hypertrophic Cardiomyopathy versus Storage Diseases with Myocardial Involvement

“…Recently, Park et al conducted a study with a genome-first approach; the total sample size of 41,759 subjects was analyzed by whole exome sequencing (WES), and the results were then compared with their clinical data [31]. Subsequent analysis showed that only 38.5% of patients diagnosed with HCM (with a pathogenic variant in MYBPC3 or MYH7) had genetic testing performed at diagnosis.…”

“…Subsequent analysis showed that only 38.5% of patients diagnosed with HCM (with a pathogenic variant in MYBPC3 or MYH7) had genetic testing performed at diagnosis. This means that in more than 60% of these patients, pathogenic variants could be detected by a genome-first approach [31]. It showed also the importance of evaluating novel variants in human genome research, both predicted loss-of-function (pLOF) and predicted deleterious missense (pDM) [31].…”

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum

“…We meta-analyzed results from gene-based group tests for rare predicted loss-of-function (pLoF) variants using SAIGE-GENE 26 (Figure 3) for 20,675 participants with and 287,123 participants without HF from the EUR population and 6,533 participants with and 62,003 participants without HF from the AFR population. Because missense variants may produce distinct consequences compared to pLoF variants 27 , we repeated the gene-based analysis, testing associations with carrier status for a predicted damaging missense variant and all-cause HF.…”