Typical and atypical ADPKD: predicted pathogenic genetic variants and population frequencies

The population frequency of AD polycystic kidney disease (ADPKD) has not been known with certainty. We hypothesized that more accurate population frequencies for typical (PKD1, PKD2) and atypical (GANAB, ALG9, DNAJB11 ALG5, IFT140, NEK8) ADPKD were possible using a computational approach.

Initially, this study calculated the number of predicted pathogenic structural, null, and missense variants in the ADPKD-associated genes in gnomAD v.2.1.1, and compared this with disease-causing changes according to the ClinVar, HGMD, or LOVD databases. However, because of the difficulty assessing missense variant pathogenicity, ClinVar assessments were used instead for gnomAD v.4.1, which includes a larger cohort, and more structural and copy number data.

Predicted pathogenic variants were found in the typical ADPKD genes in 1 in 314 people, with PKD1 and PKD2 changes present in 1 in 417 and 916, respectively, using ClinVar assessments of gnomAD v.4.1 variants and loss-of-function structural and copy number changes. Predicted pathogenic null and missense variants in the atypical ADPKD genes were found in 1 in 283 people in gnomAD v.4.1 using ClinVar. No pathogenic missense changes in the kinase domain of NEK8 previously-reported in monoallelic disease were present.

Predicted pathogenic variants in the genes associated with typical and atypical ADPKD are more common than suspected previously. Predicted pathogenic variants are more common for atypical than for typical ADPKD, especially when loss-of-function structural and copy number variants are included.