Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis

Background. Juvenile nephronophthisis (NPH1), an autosomal recessive cystic disease of the kidney, represents the most common genetic cause of end-sta ge renal disease in the first two decades of life. On the basis of identifi cation of the gene (NPHP1) defective in NPH1 and the presence of homozygous deletions of NPHP1 in the majority of NPH1 patients, molecular genetic dia gnosis for NPH1 is now possible. Molecular genetic testing offers the only method for definite diagnosis of NPH1 and avoids invasive diagnostic measur es like renal biopsy. Methods. We examined 127 families (204 patients) with the presumed diagnosi s of NPH using molecular genetic diagnostic techniques. In 68 families, ren al biopsy was performed and was consistent with NPH. and in 61 families, th ere was more than one affected child ("multiplex families"). Results. In 74 families (115 patients), there was proof of the diagnosis of NPH1 by detection of a homozygous deletion of the NPHP1 gene, and in 5 fam ilies a heterozygous deletion in combination with a point mutation in NPHP1 was demonstrated. Furthermore, for 16 families, NPH1 was excluded with hig h likelihood by linkage analysis, and for 20 families by detection of heter ozygosity for two newly identified polymorphic markers within the deletion region. In 5 of the remaining 12 families, which were noninformative for th ese markers, fluorescence in situ hybridization did not detect any further heterozygous deletions. Conclusions. The diagnosis of NPH1 was proven by molecular genetic techniqu es in 62% of families with one or more children with the presumed diagnosis of NPH, We present evidence that there is a fourth locus for NPH, since on ly 6 of the 26 multiplex families in whom the diagnosis of NPH1 was exclude d were compatible with linkage to other loci for NPH. On the basis of the p resented data, we propose an algorithm for molecular genetic diagnostics in NPH.