MYH7-MYBPC3 Mutation Severity Score Calculator

MYH7/MYBPC3 Mutation Severity Score - Explanation, clinical context and references This prototype score aggregates genotype (gene and variant class), allele status (heterozygous vs compound/biallelic), family history of sudden cardiac death, age at diagnosis, maximal left ventricular wall thickness, arrhythmic markers (non-sustained ventricular tachycardia), recent unexplained syncope, left ventricular outflow tract obstruction, and atrial fibrillation to produce a normalized 0–100 severity index. The scheme assigns higher weights to features repeatedly associated with earlier onset or worsened phenotype in the literature: MYH7 variants are commonly reported with earlier onset and more severe hypertrophy in many cohorts compared with other sarcomeric genes; MYBPC3 frequently harbors truncating variants that act via haploinsufficiency but may show variable expressivity. Compound heterozygosity or biallelic pathogenic variants are reported to produce markedly more severe phenotypes.

Maximal LV wall thickness >30 mm, family history of SCD, NSVT, and unexplained syncope are established markers associated with increased risk of adverse outcomes in hypertrophic cardiomyopathy and therefore are weighted heavily in the score. This tool is intended to assist research, teaching and internal triage but must not replace guideline-directed risk stratification or specialist clinical/genetic evaluation. Selected key references (informing the score construction): Genetic determinants and phenotype differences for MYH7 and MYBPC3 - reviews and cohort analyses describing genotype–phenotype associations and differences in onset/severity.

MYBPC3 reviews on truncating variants, haploinsufficiency, and clinical variability. Meta-analyses / penetrance estimates and genotype comparisons. Biallelic/compound heterozygous cases associated with severe cardiomyopathy phenotypes.

Major guideline risk markers for sudden cardiac death (maximal LV wall thickness >30 mm, family history of SCD, NSVT, unexplained syncope, LV systolic dysfunction, apical aneurysm, extensive LGE) cited in ESC / AHA-ACC guidance and validations - these informed the selection and weight of clinical markers in the score. Practical considerations: This instrument merges genetic and clinical features into a single index for prototyping only. It does NOT include CMR LGE extent or polygenic background - both important contributors to penetrance and prognosis in recent literature (polygenic risk scores may further stratify risk when combined with rare variant data).

For the most accurate clinical risk estimation follow existing guideline algorithms (ESC HCM 2014 / AHA/ACC 2020) and incorporate comprehensive imaging (including CMR) and ambulatory ECG monitoring. Reference list: Velicki L, et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

BMC Cardiovasc Disord. 2020. Höller V, et al.

Myocardial deformation analysis in MYBPC3 and MYH7 mutation carriers. (PMC) 2021. Tudurachi BS, et al. An update on MYBPC3 gene mutation in hypertrophic cardiomyopathy.

Int J Mol Sci. 2023. Sedaghat-Hamedani F, et al.

Meta-analysis / penetrance (see recent circulation analyses). 2023. Kolokotronis K, et al.

Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy. Hum Mutat. 2019.

2014 ESC Guidelines on HCM; 2020 AHA/ACC HCM Guideline - risk factors and markers for sudden cardiac death (max wall thickness >30 mm, family history, NSVT, unexplained syncope).