From Genotype to Cardiac Phenotype: Cardiovascular Involvement in Syndromic and Metabolic Disorders

Cardiovascular disease is a leading cause of morbidity and premature mortality in many inherited syndromic and metabolic disorders. However, its cardiac manifestations are often recognized late and are rarely described collectively within a single cohort. We reviewed eight years of outsourced next-generation sequencing (NGS) requested through the pediatric genetics service of a single tertiary center in Taiwan and identified 22 patients with molecularly confirmed genetic disorders and documented cardiovascular involvement. For each patient, the causative genotype-including lysosomal storage diseases, RASopathies, CHARGE syndrome, connective-tissue disorders, primary cardiomyopathies and channelopathies, neuromuscular disorders, contiguous-gene syndromes, and other metabolic and syndromic conditions-was mapped to a structured echocardiographic phenotype. Septal defects or shunts and valvular regurgitation were the most common findings (10/22 and 9/22, respectively), followed by septal hypertrophy, valvular stenosis, and great-vessel or aortic abnormalities. Two children had left ventricular systolic dysfunction, and one died following an out-of-hospital cardiac arrest. Several cardiac lesions clustered by disease category, most notably valvular thickening in mucopolysaccharidoses and elastin arteriopathy in Williams-Beuren syndrome. These genotype-to-cardiac phenotype patterns support the need for gene-informed, systematic cardiac surveillance rather than symptom-driven referral in children with these disorders.