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

Abstract

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.