PO13 Multiple Molecular Diagnoses in a Complex Cardiac–Neurologic Phenotype: MT-TL1–Related HCM with Encephalomyopathy and TTN-Related DCM

Background Syndromic hypertrophic cardiomyopathy (HCM), especially in childhood, should always prompt consideration of a non-classical, non-sarcomeric etiology. Therefore, the diagnostic approach in such cases should rely on comprehensive genomic testing rather than targeted sarcomeric gene panels alone. Limiting diagnostics to a single presumed genetic cause may obscure the overall picture and lead to incomplete conclusions. This is particularly relevant given that multiple molecular diagnoses are reported in up to ∼4% of patients with genetically determined disorders. Objective To present a case of a patient with a complex cardio-neurologic phenotype caused by a dual molecular diagnosis involving a pathogenic MT-TL1 variant leading to hypertrophic cardiomyopathy with encephalomyopathy, and a pathogenic TTN variant linked to dilated cardiomyopathy. Methods We present the case of an 8-year-old girl, born prematurely, in whom hypertrophic cardiomyopathy was diagnosed at 5 months of age. Clinical evaluation revealed hypotonia, dysmorphic features with a myopathic facial appearance, and delayed psychomotor development. Additionally, MRI demonstrated abnormalities. Laboratory tests showed elevated lactate levels. The family history was significantly burdened with heart disease, including left ventricular dilated and other structural abnormalities observed across several generations. Conclusions This case highlights that restricting genetic diagnostics to targeted panels may result in missed pathogenic variants and an incomplete understanding of the clinical picture. Comprehensive genomic approaches, such as exome or genome sequencing, can uncover dual or multiple molecular diagnoses, provide a more accurate explanation of complex phenotypes, and guide optimized patient management, surveillance, and genetic counseling.