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Valvular dystrophies due to myxoid degeneration are common and potentially serious cardiac pathologies. They constitute a heterogeneous group of which the most usual is idiopathic mitral valvular prolapse (Barlow's disease). The majority of mitral valvular prolapses are sporadic, but there are several familial forms. Transmission is usually autosomal dominant with incomplete penetrance and variable expression. The first chromosomal location to be identified was on the 16p11-13 chromosome. Since then, two other loci have been identified on the 11p15.4 and 13q31-32 chromosomes. Our team has recently identified the first gene responsible for myxoid valvulopathy linked to the X chromosome, from a large family of 318 members. This is the gene that codes for filamin A, which is a cytoskeleton protein. The frequency of mutations in this gene is still unknown, but out of 7 families in which transmission was compatible with X-linked transmission, mutations were discovered in 4 of the families. Thanks to a genetic epidemiological approach, we have also demonstrated that there are familial forms of aortic stenosis, which are probably common. Identification of the genes implicated in these common forms of valvular pathology is important, as it will allow a better understanding of the pathophysiology of these valvular disorders and could lead to better therapeutic management in the future.

The identification of the first gene locus of hereditary arrhythmias was made over 10 years ago. In the last few years, considerable progress has been made and the number of culprit genes for cardiac arrhythmias has rapidly increased. This has been the fruit of close collaboration between clinicians, geneticists and physiologists. This work has demonstrated the heterogenous nature of genetics of diseases. It has led to a better understanding of underlying physiopathological mechanisms by the study of the relationship between gene and clinical abnormalities. In addition, analysis of phenotypes and genotypes has improved our knowledge of the clinical presentation of diseases and opened up new therapeutic approaches. These new diagnostic methods have enabled preventive measures to be taken to avoid potentially serious arrhythmias. The genetics of cardiac arrhythmias is still in its infancy: many culprit genes remain undetected and their identification should led to considerable progress in the understanding of the physiopathology of arrhythmias and their treatment.

Degenerative conduction defects are usually considered to be exaggerated ageing affecting the conduction pathways. For several years familial forms have been described, and a first locus on chromosome 19 and then a first gene, SCN5A on chromosome 3 (coding for the sodium channel alpha subunit), have been identified. Mutations of this gene can lead not only to congenital conduction defects but also to progressive forms of conduction defects similar to Lenègre disease. A third locus on chromosome 16 at 16q23-24 has been identified, as have other families not linked to the loci described previously. Although it now seems clear that conduction defects can have a genetic component, the frequency of the familial forms remains to be determined. Important progress could be made in the understanding of this disease if other implicated genes were identified. It would then become possible to elucidate the different pathophysiological mechanisms responsible for conduction defects.

Molecular genetic studies have transformed our understanding of the congenital long QT syndromes. Previously, the phenotypes of the Jervell and Lange-Nielsen and Romano-Ward syndromes were characterised by prolongation of the QTc interval greater than 0.44 seconds on the ECG and by syncope or sudden death favorised by stress, the two syndromes being differentiated one from the other by their modes of transmission, recessive or dominant, and by the presence or absence of deafness. Close collaboration between physicians, geneticians and physiologists and the use of inverse genetic techniques led to the localisation of four genes on chromosomes 11, 7, 3 and 4 to the identification of three genes coding for potassium (HERG and KVLQT1) and sodium (SCN5A) channels. These advances have not only improved our understanding of the physiopathology of these syndromes but also our phenotype criteria whilst demonstrating the complexity of clinical diagnosis. They open up new perspectives for the management of patients with these syndromes.

Progress in molecular biology has advanced our medical knowledge. The identification of genetic abnormalities has been transformed into the new approach of "inverse genetic s" which is based on close collaboration between clinicians, geneticians, molecular biologists and physiologists. In monogenic affections of unknown mechanism, the scientific method of determining the culprit gene is based essentially on precise phenotypic identification of all members of a large family and on DNA studies. The following steps consist in localising the gene with polymorphic genetic probes and then demonstrate the causal mutations and, finally, reexpress the normal and abnormal genes to study their function and thereby confirm the mutation. This approach has recently been applied to cardiac arrhythmias. Genes responsible for atrioventricular conduction defects, Wolff-Parkinson-White syndromes associated with hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia have been localised in the human genome showing that these syndromes are often very variable. The greatest progress has been achieved in the congenital long QT syndrome. Four genes have been localised on chromosomes 3, 1, 7 and 11, and three have already been identified which has allowed study of their function and genotype-phenotype analysis.