A novel frameshift variation of PKD1 in familial autosomal dominant polycystic kidney diseases: expanding the clinical phenotype and genetic spectrum of PKD1 disorders

Autosomal dominant polycystic kidney disease is a common monogenic hereditary kidney disorder. Mutations in the PKD1 gene lead to the development of fluid-filled cysts in the kidney, liver, and other organs, which can eventually result in end-stage renal failure. Affected individuals have a 50% chance of passing the mutation to each of their offspring. Families with ADPKD are advised to undergo genetic testing to causative variants and would benefit from genetic counseling to reduce the inherited risk. We performed genetic analysis on a family with ADPKD. DNA samples extracted from the peripheral blood of ADPKD patients were subjected to whole exome sequencing (WES) analysis. Variations were assessed in accordance with the American College of Medical Genetics and Genomic (ACMG) guidelines. Moreover, recent literature focusing on newly identified pathogenic PKD1 mutations and their clinical manifestations was summarized in this study. A novel heterozygous variant in the PKD1 gene [NM_001009944.2, c. 5733_5751dup GGCTGCCGGCTCAGCTGTC (p.Thr1918Glyfs*78)] was identified. The variant was absent in published database and resulted in a frameshift mutation predicted to lead to premature termination of the protein translation. The comprehensive analysis of population frequency, conservation, structural and pathogenicity prediction suggested that this variant was classified as pathogenic. This is the first reported ADPKD case caused by this novel PKD1 variant. This finding expands the known mutation spectrum of the PKD1 genes and provides a foundation for genetic counseling and future preimplantation genetic diagnosis in affected families. Our findings offer valuable genetic and clinical insights for accurate diagnosis and evaluation of disease progression.