Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Abstract

Purpose: To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010-2020).

Methods: All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing.

Results: Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%).

Conclusion: We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.

Fig. 1. Summary of referrals for genetic testing in 51 infants presenting under 18 months of age between 2010 and 2020 and the main results.

Of the 21 infants with biallelic variants, 20 were tested for other cystic genes either through a 17-gene panel or exome or genome sequencing.

Fig. 2. Structural modeling of PC1 hypomorphic variants.

a Lollipop plot showing missense variants relative to a schematic representation of the PC1 protein. Any position with a variant is indicated by a red circle, the gray bar represents the protein with the different amino acid positions (aa), and colored boxes are specific functional domains. b Ribbon diagram of PC1 showing the representative missense variant residues in red. Dashed boxes correspond local impacts of variants on PC1 structure. Interactions are labeled as black dashed lines (pseudobonds), H-bonds are labeled in purple and Interatomic distances are expressed in Å.

Fig. 3. Nuclear magnetic resonance (NMR) model of the PC1 PLAT domain with surface mapping of specific ligand-binding residues.

a Membrane-facing side showing phosphatidylserine, PS (stick), Ca²⁺ (orange sphere). Surface representation indicating residues binding PS (light blue) and β-arrestin1/2 (pink). The key Ser3164 residue (red) which modulates PI4P and β-arrestin1/2 binding is indicated. b Cytoplasmic-facing surface of PLAT showing a predicted protein interaction domain (deep blue). Several residues identified to be altered in this study are labeled (orange) and mapped onto this model, i.e., E3121, I3167, G3150, and N3188. Note the close proximity of E3121 and 13167 to the same Ca²⁺−dependent PS-binding pocket. E3121 also forms part of a functional YEIL³¹²³ motif involved in AP2-mediated internalization of PC1..