Phenotypic Discordance among Siblings with Autosomal Recessive Polycystic Kidney Disease: Case Report and Review of the Literature

Abstract

Missense variants in the PKHD1 gene are associated with the full spectrum of autosomal recessive polycystic kidney disease severity and exhibit variable expressivity. The study of clinical expressivity is limited by the extensive allelic heterogeneity within the PKHD1 gene, which encodes a 4074-amino-acid protein. We report the case of adult siblings with biallelic missense PKHD1 variants, c.4870C>T (p.Arg1624Trp) and c.8206T>G (p.Trp2736Gly), who presented with discordant phenotypes. Patient A developed progressive chronic kidney disease and Caroli syndrome in childhood requiring combined liver and kidney transplantation, while patient B remains minimally affected in the fourth decade of life with normal kidney function and signs of medullary sponge kidney on imaging. We review previously reported cases of phenotypic discordance among siblings and suggest that genotypes composed of at least one hypomorphic missense variant are more likely to lead to phenotypic discordance.

Keywords: Autosomal recessive polycystic kidney disease; Caroli syndrome; Medullary sponge kidney.

Fig. 1.

a Proband pedigree. b Axial MRI of patient A showing dilated intrahepatic bile ducts. c Coronal MRI of patient A showing splenomegaly and small kidneys with numerous cysts suggestive of polycystic kidney disease. d Coronal MRI of patient B showing atrophic left kidney and hypertrophic right kidney with signs of medullary sponge kidney.

Fig. 2.

Multiple sequence alignment of vertebrate PKHD1 orthologous proteins obtained from the Ensembl Compara database. The arginine at position 1,624 is conserved in most primates. The tryptophan at position 2,736 is conserved in most vertebrates.

Fig. 3.

Comparison of genotypes from discordant sibships to those from an ARPKD reference cohort [15]. Top: predicted pathogenicity by AlphaMissense for missense alleles A and B of genotype A/B. Vertical and horizontal lines indicate cut-offs for benign and likely pathogenic predictions. Diagonal line indicates genotypes composed of variants with equal predicted pathogenicity. Red triangle indicates the predicted pathogenic/pathogenic zone. a Pathogenic genotypes of discordant sibships reported in the literature (Table 2). Proband genotype in red. None of the genotypes fall in the predicted pathogenic/pathogenic zone. b Pathogenic genotypes from ARPKD reference cohort. Bottom: c PKHD1 protein and its domains with pathogenic missense alleles from discordant sibships above protein and pathogenic missense alleles from ARPKD reference cohort below. AlphaMissense class: benign (green), ambiguous (orange), likely pathogenic (red). IPT/TIG, Ig-like, plexins, transcription factors/transcription factor Ig; PA14, anthrax protective antigen 14; G8, 8 conserved glycines; PbH1, parallel beta-helix repeats.