Genetics of autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder which is characterized by the formation and progressive enlargement of multiple bilateral kidney cysts. It is a relatively uncommon disorder with an estimated prevalence of 1 in 1000 to 1 in 2500 individuals. ADPKD is also associated with a high phenotypic variability even between affected members of the same family such that the age of onset and the severity of the disease differs significantly between affected individuals. Through the use of molecular testing, it is known that 80-85 % of the affected individuals possess a pathogenic variant in PKD1 and 15-20 % of the cases are characterized by a pathogenic variant in PKD2. Locally, the Malta Next Generation Sequencing Project is the first study that is being carried out to identify pathogenic variants responsible for causing ADPKD in the Maltese population. High throughput sequencing (HTS) has been performed on 18 unique pedigrees which include 15 affected adults and 3 nuclear families. Candidate variants have been identified in 16 pedigrees. However, HTS data on its own is not sufficient to determine whether the identified variants are pathogenic or benign. Therefore, this study is aiming to carry out a population study where approximately 600 cord blood DNA samples are tested to determine the allele and genotype frequencies of the selected variants using real time genotyping. The Malta NGS Project (n=179) has 105 unrelated HTS datasets and an additional 74 HTS datasets of relatives of probands. The PKD1 p.C508R polymorphism was identified in 13 individuals from the NGS study, 11 of whom were adults from 4 unrelated families without ADPKD and the remaining 2 were ADPKD patients (pedigrees 2 and 10; Cini Masini 2021). In both pedigrees, another potentially pathogenic PKD1 variant apart from the SNP of interest was found. The PKD1 p.L337Q polymorphism was identified in 2 individuals who were both ADPKD patients (pedigrees 5 and 11; Cini Masini 2021). In both pedigrees, other potentially pathogenic PKD1 variants apart from the SNP of interest were also found and, in pedigree 5, the PKD1 p.L337Q was only found in 1 of 3 family members with ADPKD. Based on the findings of this project, it can be concluded that both PKD1 p.L337Q and PKD1 p.C508R are not pathogenic, hence do not contribute to cystogenesis in ADPKD.