Génétique des cardiopathies congénitales et des cardiopathies héréditaires non myocardiques.

Abstract

La génétique moléculaire a permis d’appréhender les cardiopathies congénitales sous un angle différent. A partir d’exemples choisis, il est possible d’illustrer la conception récente de l’hérédité mendélienne des malformations cardiaques et les difficultés du clonage positionnel d’affections souvent létales, à pénétrance incomplète et subissant de grandes variations phénotypiques inter- et intrafamiliales. L’identification des microdélétions interstitielles du chromosome 22q11 dans les cardiopathies cono-troncales a ouvert plusieurs axes de recherche depuis l’embryologie jusqu’à une réflexion éthique concernant le diagnostic prénatal. Les modèles murins d’anomalie de latéralisation du coeur seront probablement à l’origine du clonage des gènes humains.

Recent progress has been made in the understanding of the mechanisms of congenital heart disease through new insights in molecular genetics in these congenital defects. Various approaches have been used towards the identification of genes responsible of cardiac malformations. Linkage analysis allowed the cloning of the Holt-Oram syndrome gene, TBX5, and mapping of a gene for familial total anomalous pulmonary venous return on chromosome 4. Genetic heterogeneity of cardiac malformation is supported by the exclusion of the Holt-Oram syndrome genetic interval in isolated familial atrial septal defect which is the main cardiac defect in Holt-Oram syndrome. Cono-truncal diseases (tetralogy of Fallot, truncus arteriosus...) are frequently associated with chromosome 22q11 microdeletion. Physical mapping of the commonly deleted region allowed the identification of different genes potentially playing a role in the conal septation. Williams syndrome (facial dysmorphy, supravalvar aortic stenosis, mental retardation) is a contiguous gene syndrome due to a microdeletion on chromosome 7q23 at the locus of the elastine gene and missense mutations have been found in non syndromic supravalvar aortic stenosis. Some clues have been found in animal models of congenital heart defects as lateralization defects associated with complex congenital heart malformations, and mutations in ZIC3 have recently been identified in X-linked heterotaxia. Fibrillin mutations were found responsible for Marfan syndrome in which genetic heterogeneity has also been demonstrated. Finally, a gene for familial isolated conduction defects was located on chromosome 19. Molecular genetics offers new perspectives in the understanding of congenital heart malformations etiology. [References: 44]