The Complex Genetic Basis of Congenital Heart Defects

Abstract

Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or inherited genetic abnormality can be identified as pathogenic in one-third of cases. We refer to them here as monogenic causes, insofar as the genetic abnormality has a readily detectable, large effect. What explains the other two-thirds? This review considers a complex genetic basis. That is, a combination of genetic mutations or variants that individually may have little or no detectable effect contribute to the pathogenesis of a heart defect. Genes in the embryo that act directly in cardiac developmental pathways have received the most attention, but genes in the mother that establish the gestational milieu via pathways related to metabolism and aging also have an effect. A growing body of evidence highlights the pathogenic significance of genetic interactions in the embryo and maternal effects that have a genetic basis. The investigation of CHD as guided by a complex genetic model could help estimate risk more precisely and logically lead to a means of prevention.

Keywords: Congenital heart defects; Genetics; Maternal age; Maternal effects; Modifier genes.

Figure

The vast majority of the known causes of congenital heart defects (CHD) are de novo or inherited genetic abnormalities. A monogenic basis can be identified in one-third of all cases. The Baltimore-Washington Infant Study and Metropolitan Atlanta Congenital Defects Program yielded similar estimates for the fraction attributable to chromosomal syndromes.^, De novo copy number variants (CNVs) include both the well-known, such as the 22q11.2 deletion, and more recently discovered ones. The fraction attributable to de novo mutations that affect protein-coding sequence were recently reported in 3 large, whole-exome sequencing studies of trios.^– The burden of inherited loss-of-function mutations of known CHD genes was estimated in one of these studies. Inherited CNVs and other forms of genetic mutation cause monogenic CHD, but their attributable fractions have not been quantified in large studies similar to the ones cited above. An oligogenic basis may explain a large fraction of the currently unknown causes.