Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases.

Figure 1.

Analysis of ARPKD-like family P990 shows it is not linked to PKHD1 and pathogenicity is associated with two hypomorphic PKD1 alleles. (A) Pedigree showing the ARPKD (position of PKHD1 shown) and the PKD1 haplotypes. Only the PKD1 haplotype, including R2220W, R3277C, and two polymorphisms (Q739R and W1399R), segregate with the disease. (B) T2-weighted magnetic resonance images of II-2 at 1 year, axial (top and middle) and coronal (bottom), demonstrating marked renal enlargement by diffuse tubular dilation and small cysts. (C) Conservation of R2220W in PC-1 orthologs showing that it is a basic amino acid in all species to Fugu.

Figure 2.

Characterization of ARPKD-like family SE44 showing the renal and biliary phenotypes and that the affected subjects are homozygous for two in cis PKD1 variants. (A) Pedigree showing the ARPKD (intragenic PKHD1 marker bolded) and PKD1 haplotypes, with the PKD1 variants V1045M and T1570M being homozygous in the two affected children. The two affected patients do not have the same PKHD1 alleles. I-1 (gray) has a few renal cysts. (B) Hematoxylin and eosin (H&E)-stained sections of a 20-week fetal kidney (III-2) demonstrating cysts. Some cysts with tuft remnants are glomerular cysts (inset). (C) Fetal kidney (20 weeks; III-2) detected with LTA (red) and DAPI (blue) shows that most cysts are of proximal tubule origin. Some cysts (arrow) are only partially stained, indicating dedifferentiation of the cyst lining. (D) This H&E-stained portal tract is mildly enlarged but appears normal. It has a discontinuous layer of ductal plate cells at the junction between the portal tract parenchyma and the hepatic lobule and the ductal plate layer shows segmental duplication with a formation of small ductular structures (arrows). A large central portal vein is apparent. (E) V1045M and T1570M are in moderately conserved positions in PC-1 orthologs to Fugu. (F) Tertiary structure modeling based on the nuclear magnetic resonance structure of the PKD domain I shows the effects of the T1570M (I294M in PKD domain I) substitution (top) and enlargement (below). The PKD domain is visualized from the bottom with the carbon backbone (light blue), hydrogen bonds (red), and structure of the altered residue (dark blue). Novel hydrogen bonds are arrowed.