The Common PKD1 p.(Ile3167Phe) Variant Is Hypomorphic and Associated with Very Early Onset, Biallelic Polycystic Kidney Disease

Abstract

Biallelic PKD1 variants, including hypomorphic variants, can cause very early onset polycystic kidney disease (VEO-PKD). A family with unexplained recurrent VEO-PKD and neonatal demise in one dizygotic twin was referred for clinical testing. Further individuals with the putative hypomorphic PKD1 variant, p.(Ile3167Phe), were identified from the UK 100,000 genomes project (100 K), UK Biobank (UKBB), and a review of the literature. We identified a likely pathogenic PKD1 missense paternal variant and the putative hypomorphic PKD1 variant from the unaffected mother in the deceased twin but only the paternal PKD1 variant in the surviving dizygotic twin. Analysis of 100 K cases identified a second family with two siblings with similar biallelic inheritance who presented at birth with VEO-PKD and reached kidney failure in their teens unlike other affected relatives. Finally, a survey of 618 UKBB cases confirmed that adult patients monoallelic for PKD1 p.(Ile3167Phe) had normal kidney function. Our data reveals that p.(Ile3167Phe) is the second most common PKD1 hypomorphic variant identified and is neutral in heterozygosity but is associated with VEO-PKD when inherited in trans with a pathogenic PKD1 variant. Care should be taken to ensure that it is not automatically filtered from sequence data for VEO cases.

Figure 1

Details of the clinical VEO-PKD pedigree. (a). Family tree showing known PKD1 genotypes with the two neonates with VEO-PKD and early demise (red). (b). Antenatal scans (top) of all 3 affected neonates at different stages of gestation: II:1 (32 weeks), II:2 (27 weeks); II:3 (27 weeks). Sequential kidney lengths (bottom) for all 3 plotted relative to the 95^th centiles for age. (c). In silico modelling of the PC1 PLAT domain by missense 3D showing the position of the hypomorphic change p.(Ile3167Phe) using 1 letter amino acid code (I3617F) due to space constraints.

Figure 2

Details of the 100 K.1 pedigree. Family tree showing the two individuals with VEO-PKD (red) and biallelic PKD1 variants p.(Thr3358Hisfs^∗32) and p.(Ile3167Phe) who reached kidney failure aged 17 and 22, respectively, within the context of other known affected individuals in the pedigree with only the p.(Thr3358Hisfs^∗32) variant and/or typical adult-onset PKD.

Figure 3

Dosage model of cyst formation. PKD1 dosage (%, y-axis) is shown to vary from 0 (2 null alleles) to 100 (2 normal alleles) and the likely age of presentation for different variants shown on the x-axis (years). The total dosage corresponding to the inheritance of each variant as monoallelic (1 normal and 1 variant allele) or biallelic (2 variant alleles) is illustrated. We predict that p.(Ile3167Phe) must have ~30% retained PC1 activity since p.(Ile3167Phe) homozygotes have been reported without kidney failure. The cystogenic threshold is assumed to be <30% functional PC1.