Hypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease

Abstract

1. Autosomal dominant polycystic kidney disease (ADPKD) manifesting earlier than expected on the basis of family history can identify clinically tolerant PKD1 alleles with reduced expression.

2. Hypomorphic PKD1 alleles can cause mild kidney disease or liver cysts in the absence of clinically manifest kidney involvement.

3. The presented data highlight pleiotropic ADPKD clinical presentations and varying severity of kidney disease from PKD1 allele combinations.

Figure 1

Clinical, familial, and genetic characteristics of probands (black arrowhead) with biallelic ADPKD. Family pedigree shown with individual identifiers (age at evaluation) and clinical information (black dot represents ADPKD-affected status on the basis of clinical/radiological criteria). PKD1 variant status^# for tested individuals and their associated kidney imaging where available (ultrasound or CT; kidney cysts—multiple: >4 to <20 on each side; innumerable: >20 count on each side; kidney size^##) and/or histopathology is shown. ^#Gene testing method used: Family Y1: whole-exome sequencing for Y1-I and Y1-II, including analysis of variants in a manually curated list of 113 genes known to associate with isolated or syndromic early renal cystic phenotype. PKD1 gene-specific long-range sequencing for identified PKD1 variants (Y1-I, Y1-II, Y1-III). Family C1: next-generation sequencing panel with CNV detection (genes included: DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, PKHD1) and PKD1 gene-specific Sanger sequencing for specific variant testing in both parents. Family C2: next-generation sequencing panel with CNV detection (genes included: DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, PKHD1) and PKD1 gene-specific Sanger sequencing for specific variant testing in both parents. Family Y2: gene-specific Sanger sequencing (genes included PKD1, PKD2). Family C3: next-generation sequencing panel with CNV detection (genes included: PKD1, PKD2, PKHD1, HNF1B), followed by PKD1 gene-specific Sanger validation of identified variants. *(red asterisk) means no genetic testing available. ^##Kidney size: defined as large for demographic parameters and normative data on the basis of “Sonographic Assessment of Renal Length in Normal Children,” Am J Roentgenol. 1984;142:467-469. CT, computed tomography.

Figure 2

Pictorial representation of PKD1 alleles that correlate with the reported ADPKD disease spectrum. (A) Gradation of the functional PKD1 gene dosage or polycystin-1 (PC1) level ranging from two healthy PKD1 alleles (PKD1^wt/wt; normal PC1 level) to complete absence of PC1 protein with PKD1 knock-out alleles (PKD1^null/null) is pictorially shown. This is on the basis of the permissive hypothesis that PKD1 hypomorphic variants and the resulting allele combinations lie across a gene-dosage spectrum that translates into a gradation of functional PC1 dosage with clinical correlations. Hypomorphic PKD1 alleles in the heterozygous form depending on their individual functional effect may associate with no cysts (Val1971Met; Asp1332Asn), liver cysts only (Val1611Ile), or fewer kidney cysts (Thr2250Met) than would be expected in a typical age-matched ADPKD course because of a definite pathogenic variant (Thr2192Alafs*18; His526Thrfs*32). In trans combinations of a hypomorphic allele with/a definite pathogenic variant (Asp1332Asn/Thr2192Alafs*18; Asp1332Asn/His526Thrfs*32), another likely pathogenic missense variant (Val1611Ile/Arg2767His; Phe2132Cys/Arg3750Gln) or another hypomorphic allele (Thr2250Met/Val1971Met) can result in early-onset ADPKD. Clinical/Imaging information not available for wt/Arg2767His or wt/Phe2132Cys combinations in this series. (Figure adapted from: Gallagher AR, Germino GG, Somlo S. Molecular advances in autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis. 2010;17(2):118-130).