Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease (prevalence 1:200 - 1:500), manifested by thickening of cardiac walls, increasing risks of arrhythmia, and sudden cardiac death. HCM affects all ages - it is the leading cause of death among young athletes. Comorbidities due to gene mutations include altered vascular control, and, caused by HCM, ischemia, stroke, dementia, or psychological and social difficulties. Multiple causal mutations and variations in cellular processes lead to highly diverse phenotypes and disease progression. However, HCM is still diagnosed as one single disease, leading to suboptimal care. SMASH-HCM will develop a digital-twin platform to dramatically improve HCM stratification and disease management, both for clinicians and patients. Multilevel and multiorgan dynamic biophysical and data-driven models are integrated in a three-level deep phenotyping approach designed for fast uptake into the clinical workflow. SMASH-HCM unites 8 research partners, 3 hospitals, 3 SMEs, and a global health-technology corporation in collaboration with patients to advance the state of the art in human digital-twins: including in-vitro tools, in-silico from molecular to systemic level models, structured and unstructured data analysis, explainable artificial intelligence - all integrated into a decision support solution for both healthcare professionals and patients. SMASH-HCM delivers new insights into HCM, improved patient care and guidance, validated preclinical tools, and above all, a first HCM stratification and management strategy, validated in a pilot clinical trial, and tested with end users. Thus providing a cost efficient and effective solution for this complex disease. SMASH-HCM develops a strategy towards fast regulatory approval. In reaching its goals, SMASH-HCM serves as a basis for future digital-twin platforms for other cardiac diseases integrating models and data from various scales and sources.