The following is a summary of ‘’Atypical splicing variants in PKD1 explain most undiagnosed typical familial ADPKD,” published in the July 2023 issue of Nephrology by Hort et al.

Autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of kidney failure, involves PKD1 or PKD2, and 10% remain undiagnosed.

Researchers performed a retrospective study utilizing short and long-read genome sequencing and RNA analysis to examine undiagnosed families with typical ADPKD phenotypes. Unidentified patients displaying the typical characteristics of ADPKD were enrolled.

Patients underwent multiple genetic analyses, including short-read genome sequencing, analysis of PKD1 and PKD2 genes, and genome-wide analysis. Those who remained undiagnosed after initial tests underwent long-read genome sequencing using Oxford Nanopore Technologies.

Of 172 individuals studied, 9 met the necessary criteria and agreed to participate. A genetic diagnosis was successfully made in 8 out of these 9 families (89%) who had previously remained undiagnosed despite prior genetic testing. Among these families, 6 had variants that affected the splicing process, with 5 of them found in non-coding regions of the PKD1 gene. Through short-read genome sequencing, previously unidentified variations were discovered, including a novel branchpoint, AG-exclusion zone, missense variants leading to the creation of hidden splice sites, and a deletion causing significant shortening of an important intron. The diagnosis was further confirmed in one family through long-read sequencing. These findings indicated that most families with typical ADPKD and an undetermined genetic cause have variants in PKD1 that impact splicing.

This study presented a practical approach for diagnostic labs to evaluate non-coding PKD1 and PKD2 regions and confirm suspected splicing variants using targeted RNA analysis.

Source: nature.com/articles/s41525-023-00362-z