There is extreme variability in the expression of ADPKD both between and within families. The factors contributing to these differences are largely unknown, but could be used to predict and potentially alter the clinical outcome of PKD mutations. The between-family variability could be due to locus heterogeneity, to allelic heterogeneity for mutations or wild-type alleles, and/or modifier genes. The within-family variability cannot be explained by either locus heterogeneity or by allelic heterogeneity for mutations, but could be due to allelic heterogeneity for wild-type PKD alleles or modifier genes. This study will use a large collection of clinically well-characterized ADPKD families to determine the effects of wild-type PKD alleles and modifier genes on phenotypic expression. Evidence supporting a 2-hit model of cystogenesis involving a somatic mutation in the wild-type and a distinct pattern of familial correlations for phenotypes relating to the timing and development of cysts, suggest a model in which different wild-type PKD alleles are associated with different somatic mutation rates. The model will be tested in Specific Aim 1 by determining if siblings who inherit the same wild-type PKD allele are more similar than siblings who inherit a different wild-type PKD allele. If so, association studies will be used to identify the specific wild-type PKD allele(s) that have a high somatic mutation rate(s). The pattern of familial correlations for other clinically-relevant ADPKD- related phenotypes, such as creatinine clearance, age at ESRD, and hypertension is consistent with the effects of modifier genes. However, the number of candidate modifier genes among known genes is very large; and one or more as yet unidentified genes could also be involved. Therefore, in Specific Aim 2, a genome screen for linkage will be used to identify positional candidate modifier genes, focusing initially on a subset of the most highly discordant families, followed by replication in families with severe phenotypes. Additional markers in regions where significant linkage is found in both samples will then be typed in all families in order to pinpoint the specific modifier gene(s). A final analysis will be performed to estimate the relative influence of different sources of phenotypic variability, and to investigate the genetic and environmental correlations among different phenotypes.
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