Familial phenotype differences in PKD11.
Familial phenotype differences in PKD1.


BACKGROUND
Mutations within the PKD1 gene are responsible for the most common and most severe form of autosomal dominant polycystic kidney disease (ADPKD). Although it is known that there is a wide range of disease severity within PKD1 families, it is uncertain whether differences in clinical severity also occur among PKD1 families.


METHODS
Ten large South Wales ADPKD families with at least 12 affected members were included in the study. From affected members, clinical information was obtained, including survival data and the presence of ADPKD-associated complications. Family members who were at risk of having inherited ADPKD but were proven to be non-affected were included as controls. Linkage and haplotype analysis were performed with highly polymorphic microsatellite markers closely linked to the PKD1 gene. Survival data were analyzed by the Kaplan-Meier method and the log rank test. Logistic regression analysis was used to test for differences in complication rates between families.


RESULTS
Haplotype analysis revealed that each family had PKD1-linked disease with a unique disease-associated haplotype. Interfamily differences were observed in overall survival (P = 0.0004), renal survival (P = 0.0001), hypertension prevalence (P = 0.013), and hernia (P = 0.048). Individuals with hypertension had significantly worse overall (P = 0.0085) and renal (P = 0.03) survival compared with those without hypertension. No statistically significant differences in the prevalence of hypertension and hernia were observed among controls.


CONCLUSIONS
We conclude that phenotype differences exist between PKD1 families, which, on the basis of having unique disease-associated haplotypes, are likely to be associated with a heterogeneous range of underlying PKD1 mutations.
Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, United Kingdom. Hateboer@Cardiff.AC.UK
N
N
Hateboer
L P
LP
Lazarou
A J
AJ
Williams
P
P
Holmans
D
D
Ravine
D008040:Genetic Linkage / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006417:Hematuria / Q000453:epidemiology / Q000209:etiology; D006555:Hernia, Ventral / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000209:etiology; D007669:Kidney Calculi / Q000453:epidemiology / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000209:etiology; D018895:Microsatellite Repeats; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications / Q000235:genetics; D015995:Prevalence; D011506:Proteins / Q000235:genetics*; D016019:Survival Analysis; D050396:TRPP Cation Channels
D011506:Proteins; D050396:TRPP Cation Channels