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Beyond the heart: minor phenotypic features and their diagnostic value in cardiogenetics

Cardiogenetics is an emerging field focusing on inherited heart disorders. While many conditions primarily affect the heart, some present with subtle extracardiac features that can be diagnostically informative. We report three cases where such findings - combined with molecular analysis - were decisive in establishing the diagnosis, illustrating the value of phenotypic characterization in cardiogenetic diagnosis.

Clinical, molecular, and family history data were collected during cardiogenetics consultations. A next-generation sequencing (NGS) cardiomyopathy panel was performed in all index patients, followed by segregation studies in relatives. Phenotypic findings were correlated with genetic variants.

Case 1: A 15-year-old male with recurrent myocarditis-like episodes presented with woolly hair and plantar keratoderma. Genetic testing identified a maternally inherited, likely pathogenic DSP (NM_004415.4) nonsense variant [c.2917G>T p.(Glu973*)], consistent with arrhythmogenic cardiomyopathy, woolly hair, keratoderma, and tooth agenesis.

A 17-month-old boy with hypotonia and epilepsy carried a pathogenic DSP (NM_004415.4) nonsense variant [c.1273C>T p.(Arg425*)], inherited from his father. Although the proband's cardiac evaluation was normal, family history disclosed myocarditis, woolly hair, and keratoderma in the paternal lineage, consistent with a cardio-cutaneous phenotype.

A father and son, both presenting with dilated cardiomyopathy and distal arthrogryposis, were found to harbour a novel ACTC1 (NM_005159.5) missense variant [c.1120C>T p.(Arg374Cys)]. This variant, absent from gnomAD and predicted deleterious by REVEL (score 0.948), alters a residue previously linked to combined cardiac and skeletal muscle phenotype.

These cases underscore the potential role of phenotypic assessment in cardiogenetics. Recognition of extracardiac manifestations—such as hair, skin, and musculoskeletal anomalies—can point toward specific genetic conditions, guiding targeted testing and enabling earlier diagnosis. Thus, combining a thorough phenotype characterization with molecular analysi