Original Investigations: Pathogenesis and Treatment of Kidney Disease and Hypertension
Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease

https://doi.org/10.1053/ajkd.2002.33908Get rights and content

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 500 to 1,000 live births. Mutations in one of two genes, PKD1 and PKD2, account for the disease in most ADPKD families. Despite the relative high frequency of PKD1 mutant alleles, compound heterozygotes or diseased homozygotes have not been described. Methods and Results: We report a family with type 1 ADPKD in which the marriage between affected first-degree cousins resulted in two live-born heterozygous offspring and two fetuses lost in late pregnancy. Genetic analysis with PKD1 and PKD2 flanking markers showed that this family is PKD1 linked (zmax = 1.66 and −2.54 at θ = 0.0 for intragenic markers for PKD1 [ie, KG8] and PKD2 [ie, SPP1], respectively). Conclusion: Given a 25% chance for mutant homozygosity in the offspring of this family, our findings suggest that homozygosity of PKD1 mutations in humans is embryonically lethal, as recently documented in Pkd1 knockout mice. © 2002 by the National Kidney Foundation, Inc.

Section snippets

TOR72 pedigree

In the course of ascertaining more than 250 ADPKD families for genetic studies, we identified a white family (TOR72) in which consanguinous marriage between affected first-degree cousins was clearly documented (III:2 and III:3, Fig 1).

. Pedigree structure and PKD1 haplotypes in TOR72. The consanguinous marriage between III:2 and III:3 is denoted by a double horizontal bar. Two spontaneous miscarriages of the proband (III:2) are shown as small triangles. Age at last ultrasound examination

Results

Three of the affected members of TOR72 (ie, III:2, III:3, and III:4) developed end-stage renal disease at 58, 66, and 59 years of age, respectively. Disease severity in these individuals was typical of type 1 ADPKD.17 This clinical impression was confirmed by pairwise linkage results (Table 1), which were consistent with linkage to PKD1 (Zmax = 1.66, θ = 0.00 for KG8), but not PKD2 (Zmax = −2.54, θ = 0.00 for SPP1).

. Pairwise Linkage Analysis for ADPKD in TOR72 Using Markers Flanking PKD1

Discussion

Given that ADPKD affects between 1 in 500 to 1,000 live births, bilineal disease is predicted to occur in approximately 1 in 250,000 to 1,000,000 marriages in the general population.17, 18 This likelihood is increased further in populations in which consanguinous marriage is prevalent. A potential consequence of bilineal ADPKD is that some of the affected members from these pedigrees may carry two germline mutations. Two scenarios may result. First, in families in which germline mutations of

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    Supported in part by the Kidney Foundation of Canada.

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