Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

Aarhus University Hospital Denmark

Biostatistique et Informatique Médicale U423 Hôpital Necker Enfants Malades Université René Descartes Paris France

Charles University Prague Czech Republic

Curry Cabral Hospital Lisbonne Portugal

Fundación Valenciana de Investigaciones Biomédicas Instituto de Investigaciones Citológicas Valencia Spain

Guy's Hospital University of London United Kingdom

Hospital Köln Merheim Cologne Germany

Institut Nationale de la Santé et de la Recherche Médicale U423 Hôpital Necker Enfants Malades Université René Descartes Paris France

Jagiellonian University Medical School Krakow Poland

Karolinska Institute Stockholm Sweden

The Italian Multicenter Study on Alport Syndrome Italy

Université Catholique de Louvain Belgium

University Hospital Lund Sweden

University Hospital of Nijmegen The Netherlands

University of Maastricht The Netherlands

References provided by Crossref.org

A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people

Guidelines for Genetic Testing and Management of Alport Syndrome