PKD1 Splice and PKD2 Nonsense Variants Identified in Two Chinese Families With Autosomal Dominant Polycystic Kidney Disease

Aim Autosomal dominant polycystic kidney disease (ADPKD), the most common form of PKD, is a prevalent monogenic multi‐system disorder, characterised by progressive enlargement of fluid‐filled cysts. This study was designed to identify the underlying genetic causes in two ADPKD‐afflicted Han‐Chinese families. Methods A total of 10 individuals from two ADPKD‐afflicted Han‐Chinese families were recruited. Whole exome sequencing and Sanger sequencing were performed to identify possible causal variants. In silico analysis for variants' pathogenicity was performed, and an in vitro minigene splicing system was further utilised to assess the effect of the splice variant on pre‐mRNA splicing. Results A heterozygous splice variant, c.11538‐2A>G, in the polycystin 1, transient receptor potential channel interacting gene ( PKD1 ), and a novel heterozygous nonsense variant, c.2387T>G [p.(Leu796*)], in the polycystin 2, transient receptor potential cation channel gene ( PKD2 ), were identified in probands of the two ADPKD families, respectively, as well as the affected individuals, confirmed by Sanger sequencing. In silico analysis predicted these variants to be deleterious. In vitro minigene splicing assay established that the c.11538‐2A>G variant could cause complete exon 42 skipping, which was predicted to lead to a truncated protein. Conclusion A splice variant, c.11538‐2A>G, in the PKD1 gene and a novel nonsense variant, c.2387T>G [p.(Leu796*)], in the PKD2 gene were identified as the genetic drivers of ADPKD in two Han‐Chinese families, respectively. This study may help pave the way to illustrate the underlying mechanism of ADPKD and possibly provide some new clues for specific management and therapeutics.