Familial risks of congenital heart defect assessed in a population‐based epidemiologic study

TLDR

Congenital heart defects are a heterogeneous group caused by chromosomal abnormalities, Mendelian disorders, teratogenic exposures, and unknown mechanisms, with isolated defects presumed multifactorial and prior familial risk studies potentially biased. This population‑based study examined all infant CHD cases and a control birth cohort in the Baltimore‑Washington area, estimating first‑degree relative risks by grouping defects according to a pathogenic classification scheme. Precursor risks differed across defect groups, with flow lesions showing higher risks than previously reported, a 13.5 % sibling risk for hypoplastic left heart syndrome comparable to an autosomal recessive expectation, and variable ventricular septal defect risks, indicating that an additive multifactorial model does not fully explain isolated CHD of unknown etiology.

Abstract

Abstract Congenital heart defects (CHD) represent a heterogeneous group of disorders caused by chromosome abnormalities, mendelian disorders, teratogenic expo‐sures, and unknown etiologic mechanisms. A large group of various isolated defects is presumably multifactorial in origin. Previous studies of familial risks for specific anatomic defects obtained from clinical series may include significant biases and obscured pathogenic relationships. In this population‐based study we analyzed all cases of CHD in infants and a control birth cohort in the Baltimore‐Washington area. The rates of CHD were defined for first‐degree relatives of cases with isolated defects, grouped by a pathogenic classification scheme. Pre‐currence risks were found to vary among the groups, and risks for flow lesions were higher than previously reported. The sibling precurrence risk for hypoplastic left heart syndrome (13.5%) was not significantly different from that expected for an autosomal recessive mechanism; the risks for different types of ventricular septal defects (VSD) varied among mechanistic groups. The results indicate that the additive multifactorial model does not adequately account for the risks in all forms of isolated CHD of unknown etiology.