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 hypothesised 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 variant pathogenicity, ClinVar assessments were used instead for the gnomAD v.4.1 which includes a larger cohort with structural and copy number data. Predicted pathogenic variants were found in the typical ADPKD genes in one in 314 people, with PKD1 and PKD2 changes present in one in 417 and 916 respectively using ClinVar assessments of gnomADv.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 one in 283 people in gnomAD v.4.1 using ClinVar. No previously reported Gain-of- Function variants or pathogenic variants in the kinase domain of NEK8 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.