Lesion-specific familial aggregation and co-occurrence patterns of congenital heart defects: a nationwide case–control study

Background and Aims Familial clustering of congenital heart defects (CHD) is well recognised, but variation across cardiac phenotypes and kinship remains incompletely understood. We examined lesion-specific familial aggregation by distinguishing occurrence of the same broad lesion category (concordant) from different lesion categories (discordant) and described lesion co-occurrence within individuals and families. Methods We conducted a nationwide population-based case–control study including 51,778 individuals with CHD and 522,543 matched controls born in Sweden 1987-2017, with relatives identified through national registers. Lesion categories included heterotaxy, complex CHD, conotruncal defects, atrioventricular septal defect (AVSD), anomalous pulmonary venous return, left- and right-sided obstructive lesions, septal defects, valve defects, patent ductus arteriosus in term infants, other specified CHD, and unspecified CHD. Logistic regression estimated adjusted odds ratios (ORs) for concordant and discordant aggregation by lesion category and kinship. Non-hierarchical analyses examined lesion co-occurrence. Results Among lesion categories with sufficient exposed individuals, concordant aggregation was consistently stronger than discordant. The strongest concordant associations were observed for AVSD (OR 17.40, 95% CI 7.77–38.99), valve defects (13.96, 7.83–24.87), conotruncal defects (11.12, 6.59–18.75), left- and right-sided obstructive lesions. Discordant associations were elevated but lower and relatively similar across lesion categories. Concordant aggregation was higher among mothers, full siblings, and offspring, and lower among fathers and half-siblings. Multiple lesions were recorded in 19% of cases, clustering mainly within the same broad categories. Conclusions Familial CHD history carries phenotype- and kinship-specific information beyond CHD presence in relatives, supporting structured interpretation by lesion category and biological relationship.