Autosomal dominant polycystic kidney disease (
ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically,
ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for
cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop
cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed
end stage renal disease at ages 75 and 62 years, while six heterozygotes had few
cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small
cysts of relatively uniform size while marked
cyst heterogeneity is typical of
ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional
ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional
PKD1 protein may be critical for
cyst initiation.