Evidence for further genetic heterogeneity in nephronophthisis

Background. A new type of nephronophthisis (NPH) has been recently identifi ed in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsibl e gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and s econdary enuresis. Histopathological findings consist of tubular basement m embrane changes, cysts at the corticomedullary junction, and a chronic scle rosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. Methods. In order to evaluate whether there might be a fourth locus of isol ated nephronophthisis, we studied eight NPH families without extrarenal dis ease manifestations and without linkage to the NPH1 locus (NPHP1) on chromo some 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individ uals were haplotyped with microsatellites covering the genetic locus of NPH P3. Infantile NPH (NPH2) was excluded in all families by the clinical histo ry and histological findings. Results. In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by desc ent was observed. In contrast, in another four families linkage was exclude d for NPHP3. Conclusion. Four NPH-families were neither linked to NPHP1 nor to NPHP3, in dicating further genetic heterogeneity within the group of nephronophthisis . The finding of further genetic heterogeneity in NPH has important implica tions for genetic counselling.