Cardiology · Medical Literature
Geographical and Ethnic Heterogeneity in Genetic Dilated Cardiomyopathies.
Abstract
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide. Over the last few decades, significant progress has been made in understanding the genes responsible for DCM. A large number of variants have been detected, with heterogeneous distribution across the globe. Based on a systematic review of the available data, this review aims to investigate what we actually know about genetic, geographical and ethnic heterogeneity in DCM. What emerged is a disparity in clinical and instrumental valuations across different populations. Given the significant variability in the clinical and molecular presentation of these diseases, there is a need to develop an operational model that integrates technical and molecular diagnostics, imaging, and clinical capabilities tailored to the characteristics of different territories, while accounting for migratory flows and sex differences. By characterising specific genotypes, we could offer targeted therapies or contribute to the development of new care.
Clinical relevance
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide, and up to 40–50% of cases have an identifiable genetic basis, yet the vast majority of genomic registries and variant-frequency databases have been constructed from European and North American populations of predominantly White ancestry. This systematic review addresses the critical gap in understanding how genetic variant spectra, disease prevalence, clinical presentation, and penetrance differ across geographic regions, ethnic groups, and sexes — information essential for equitable precision-medicine implementation. Clinicians managing patients from underrepresented populations (African, South American, Asian, or mixed-ancestry individuals) face particular diagnostic uncertainty, as existing pathogenicity classifications may not apply reliably outside the ancestry in which they were validated.
Key findings
1. Systematic scope: A systematic literature search of PubMed, Embase, and the Cochrane Library (January 2000–2026) identified 618 records; 119 studies met eligibility criteria, providing the most comprehensive cross-population synthesis of genetic DCM to date. 2. Global genomic data disparity: No large South American genomic registries for DCM comparable to those in Europe or North America exist, and the absence of equivalently sized African registries results in a systematic underestimation of DCM incidence and prevalence in these regions. 3. Population-specific variant distributions (European): A Polish cohort of 280 DCM patients demonstrated TTN variants in 18% and LMNA variants in 8% as the dominant genetic substrate, with less frequent variants in FLNC, SCN5A, BAG3, DSP, MYH7, and DMD — a pattern broadly concordant with other European registries. 4. Population-specific variant distributions (Asian): In a Chinese WES cohort of 208 unrelated DCM patients undergoing transplantation, protein-altering variants were identified predominantly in TTN, FLNC, and LMNA, suggesting differential gene-level burden compared to Western cohorts. 5. African-ancestry-specific genetic risk: A nonsense variant (rs3211938:G) in CD36 — present in 17% of individuals of African genetic ancestry but in fewer than 0.1% of those of European ancestry — was associated with approximately threefold higher odds of DCM in homozygotes, an 8% absolute reduction in LVEF among subclinical carriers, and a population attributable fraction of 8.1%, accounting for ~20% of excess DCM risk in African-ancestry individuals. 6. Sex and ethnic interactions: Observed gender discrepancies in DCM prevalence are largely driven by a significantly higher proportion of peripartum cardiomyopathy (PPCM) cases in Black African and mixed-race groups, and additional gene–environment interactions from infections endemic to Africa (e.g., Toxoplasma gondii, HIV) may further modify DCM pathogenesis and phenotypic expression in these populations.
Practice implications
Clinicians evaluating DCM patients from non-European or non-North American ancestry should not rely exclusively on variant databases and pathogenicity thresholds derived from majority-White cohorts; ancestry-matched reference populations and local genomic registries should be sought where available, and variants of uncertain significance (VUS) should be interpreted with heightened caution in underrepresented groups. Genotype-directed risk stratification and therapy are increasingly actionable: LMNA cardiomyopathy warrants early ICD consideration (outside traditional EF-based thresholds) and is the subject of targeted gene-silencing trials (PHL-001), while gene replacement programs for BAG3 (AVB-401, phase 0) and PKP2 (TN-401, phases 0/Ib) are advancing, underscoring the urgency of accurate genetic diagnosis. An integrated operational model — combining next-generation sequencing panels, cardiac MRI with LGE characterization, sex- and migration-aware clinical algorithms, and multi-disciplinary genetic counseling — should be implemented to capture the full phenotypic and molecular spectrum of DCM across diverse patient populations.