Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Abstract

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.

Keywords: cystic kidney; human genetics; pediatrics; polycystic kidney disease.

Figure 1.

Pedigrees of patients 3 and 39 with genotypes and renal/liver histology. (A) Patient 3: renal histology shows cystic dilations involving tubules and glomeruli, regularly distributed within the parenchyma. The superficial cortex is respected. (B) Patient 39: family history shows four previous instances of early death or termination of pregnancy (TOP) for renal cystic disease (with ductal plate abnormalities in the two patients with autopsy). Renal histology of the fetus (left panel) shows large and irregularly distributed cysts, involving tubules and glomeruli. Liver histology (right panel) shows the persistence of the ductal plate. Although we were not able to test fetal DNA, the unaffected father carries three PKD1 variants, all predicted to be deleterious. Original magnification, ×10.