RAPID DNA-BASED PRENATAL-DIAGNOSIS BY GENETIC-LINKAGE IN 3 FAMILIES WITH ALPORTS-SYNDROME

Alport's syndrome (AS) is a clinically and genetically heterogeneous p rogressive inherited glomerulonephritis characterized by hematuria, se nsorineural hearing loss, ocular lesions, and specific alterations of the glomerular basement membrane. Typically, AS shows an X-linked domi nant pattern of inheritance, with mutations affecting the collagen typ e IV alpha5 chain gene (COL4A5) at Xq22. Rarely, AS is caused in some families by mutations of the COL4A3/A4 genes on chromosome 2q, showing an autosomal recessive transmission. Very few families have been desc ribed with possible autosomal dominant AS, but no mutations in any of the COL4 genes have been found. We describe three unrelated families a ffected with a severe AS phenotype in which DNA-based prenatal diagnos is by linkage analysis was made in fetuses at risk for the disease. In two families, the pedigree structure and the clinical picture were co nsistent with typical X-linked dominant AS. In these families, autosom al inheritance was also ruled out molecularly. In one family, despite careful clinical and molecular evaluation, the mode of transmission co uld not be firmly established. We used tightly linked and intragenic C OL4A5 markers, as well as COL4A3/A4-linked markers. A chromosome Y-spe cific marker for fetal sex determination was simultaneously used. In a ll the families, before the fetal analysis, the putative at-risk X hap lotype was identified with high diagnostic accuracy. We diagnosed a he althy male fetus in one family, and female but carrier fetuses in the other two kindreds, who decided not to terminate their pregnancies. We used rapid nonisotopic polymerase chain reaction-based methods, and t he results were available within 2 to 3 days. The genetic results sign ificantly affected the reproductive decisions of the parents. This rep ort illustrates the application of genetic linkage analysis as an addi tional tool for molecular diagnosis in AS, and also addresses the issu e of the attitudes of the families toward prenatal testing. To our kno wledge, prenatal diagnosis of AS using a genetic linkage approach has not been previously reported. (C) 1997 by the National Kidney Foundati on, Inc.