Recent progress in the molecular genetics of congenital heart defects

Congenital heart defects (CHD) constitute the single most common anatomic class of birth defects and are a major cause of infant mortality. Correlation of normal and pathological embryology/anatomy has led to the formulation of mechanistic models, but there is limited understanding of the genetic basis for the inferred embryological processes. Most evidence points to extensive etiologic heterogeneity and a re-evaluation of simple multifactorial models is required. The recent identification of several genes responsible for congenital heart defects in the context of more complex clinical disorders provides significant entry points for the genetic analysis of human heart development. The association of aneusomies (particularly microdeletion syndromes) with specific cardiac lesions provides further strong support for mechanistic classification. Studies in the mouse are laying the groundwork for a comprehensive genetic model of cardiac organogenesis. Nevertheless, the basis for the large majority of CHD, especially isolated defects, remains obscure. Dissection of the genetic components of CHD is one of the greatest challenges in medical genetics for the coming decades.