Hidden Genetic Disease in Coarctation of the Aorta: Insights from Whole-Genome Sequencing in a Swedish Cohort

Background : Congenital heart defects (CHDs) are the most common birth anomalies worldwide, with a substantial but incompletely characterized genetic contribution. Coarctation of the aorta (CoA) is a common CHD for which the diagnostic yield of comprehensive genomic testing remains insufficiently defined. Methods : In a single-center Swedish cohort, 19 pediatric patients with CoA with or without associated aortic arch hypoplasia, bicuspid aortic valve, or additional simple CHDs, and no prior genetic diagnosis were prospectively enrolled at the time of surgical repair and underwent whole-genome sequencing (WGS). Results : WGS identified pathogenic or likely pathogenic variants in 3/19 patients (16%), and genetic variants of uncertain significance were identified in 3/19 patients (16%). Thus, genomic findings were reported in 6 patients (32%) overall, although only the pathogenic or likely pathogenic variants were considered diagnostic. Several identified diagnoses had not been suspected based on clinical assessment alone, highlighting the limited sensitivity of phenotypic evaluation during early infancy. Conclusions : The proportion of genetically explained CoA in this surgically treated cohort supports the consideration of genetic testing, particularly in individuals with CoA accompanied by other congenital cardiac defects or extracardiac manifestations. Importantly, an underlying genetic disorder may be present despite the absence of overt clinical signs during infancy. Recognition of this possibility should encourage thorough phenotypic assessment and expanded clinical evaluation to identify potential genetic syndromes. Early genetic diagnosis may improve clinical management, surveillance, and genetic counseling for affected families.