Type of PKD1 Mutation Influences Renal Outcome in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.Autosomal dominant polycystic kidney disease (ADPKD) is the most common kidney disorder with a Mendelian inheritance pattern, with a prevalence ranging from 1/400 to 1/1000 worldwide.¹ ADPKD shows both locus and allelic heterogeneity. Two causative genes—PKD1, located at 16p13.3,² and PKD2, located at 4q21³—have been identified, and the ADPKD mutation database (http://pkdb.mayo.edu/) describes >1000 pathogenic mutations (929 in PKD1 and 167 in PKD2 as of June 5, 2012), not including our most recent data.⁴ADPKD also shows high phenotypic variability, as exemplified by the wide variation in the age at onset of ESRD,⁵ which is defined as the requirement of dialysis or transplantation. Genotype-phenotype correlation studies underscore two major issues. First, on average, ESRD occurs 20 years earlier in patients with PKD1 than those with PKD2,^6,7 indicating a genic influence on the ADPKD phenotype. Second, the position of the PKD1 mutation is associated with the age at ESRD onset,⁸ suggesting an allelic influence on ADPKD phenotype. However, these observations were made >10 years ago, when mutational analysis of the PKD1 and PKD2 genes (particularly of the nonunique portion of the PKD1 gene^2,9) was substantially less comprehensive and sophisticated than it is currently,^4,10 the methods for predicting the potential pathogenicity of missense mutations were in their infancy, and the studied patient cohorts were relatively small. To confirm (or refute) these earlier observations, we performed a genotype and phenotype correlation study using the Genkyst cohort, which comprises patients with ADPKD recruited from all private and public nephrology centers in the Brittany region, namely, the western part of France.