Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families

Background Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. Methods Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. Results In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. Conclusions Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.