From Monogenic Variants to Polygenic Risk Scores in Inherited Cardiomyopathies: Clinical Utility, Ancestry Gaps, and Future Implementation in Arab Populations

Inherited cardiomyopathies are major causes of heart failure, malignant ventricular arrhythmia, and sudden cardiac death, and they require lifelong surveillance of affected individuals and clinically at-risk relatives. Their clinical genetics has traditionally been organised around rare monogenic pathogenic or likely pathogenic variants, especially in sarcomeric hypertrophic cardiomyopathy (HCM), titin-related and other sarcomeric forms of dilated cardiomyopathy (DCM), nuclear-envelope DCM, and desmosomal arrhythmogenic cardiomyopathy (ACM). This model remains indispensable, but it is incomplete: it does not fully explain genotype-negative disease, variable penetrance, age of onset, disease severity, or discordant phenotypes within the same family. Polygenic risk scores (PRS), which aggregate the weighted effects of common variants, offer a second layer of inherited susceptibility that may refine the interpretation of rare variants and borderline phenotypes. Current evidence is strongest for HCM, increasingly important for DCM, and still weak for ACM and restrictive cardiomyopathy (RCM). The central limitation is equity and transferability. Most cardiomyopathy PRS discovery, calibration, and validation have been performed in European-ancestry datasets. At the same time, Arab and Middle Eastern populations remain underrepresented in GWAS, reference allele-frequency databases, longitudinal cardiac imaging resources, and clinical utility studies. Direct importation of European PRS into Arab cardiovascular genetics would therefore risk miscalibration, variant misclassification, false reassurance, overdiagnosis, and inappropriate counseling. This critical review evaluates PRS evidence across HCM, DCM, ACM, RCM, and related inherited cardiac diseases; explains why PRS is not a diagnostic test or replacement for monogenic testing; and proposes a phased Arab implementation framework based on local discovery cohorts, whole-genome sequencing, ancestry-aware calibration, family-based penetrance studies, harmonized imaging phenotypes, prospective outcome tracking, genetic counseling pathways, and governance safeguards. The future is not monogenic versus polygenic risk; it is integrated genomic risk, implemented only when clinically validated and equitable.