Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree

Nephronophthisis, an autosomal-recessive cystic kidney disease, is the most frequent monogenic cause for renal failure in childhood. Infantile and juv enile forms of nephronophthisis are known to originate from separate gene l oci. We describe here a new disease form, adolescent nephronophthisis, that is clearly distinct by clinical and genetic findings. In a large, 340-memb er consanguineous Venezuelan kindred, clinical symptoms and renal pathology were evaluated. Onset of terminal renal failure was compared with that in a historical sample of juvenile nephronophthisis. Onset of terminal renal f ailure in adolescent nephronophthisis occurred significantly later (median age 19 years, quartile borders 16.0 and 25.0 years) than in juvenile nephro nophthisis (median age 13.1 years, quartile borders 11.3 and 17.3 years; Wi lcoxon test P = .0069). A total-genome scan of linkage analysis was conduct ed and evaluated by LOD score and total-genome haplotype analyses. A gene l ocus for adolescent nephronophthisis was localized to a region of homozygos ity by descent, on chromosome 3q22, within a critical genetic interval of 2 .4 cM between flanking markers D3S1292 and D3S1238. The maximum LOD score f or D3S1273 was 5.90 (maximum recombination fraction .035). This locus is di fferent than that identified for juvenile nephronophthisis. These findings will have implications for diagnosis and genetic counseling in hereditary c hronic renal failure and provide the basis for identification of the respon sible gene.