Why is PKD1 important and why is it challenging to analyze?

Mutations in PKD1 cause autosomal dominant polycystic kidney disease type 1 (ADPKD1; OMIM *601313). There are a total of 1273 PKD1 variants classified as definitely pathogenic, highly likely pathogenic or likely pathogenic in the PKD1 Mutation Database.

There is no mutational hot spot for PKD1 and PKD2, which means variants are usually private, highly variable, and spread throughout the entire gene. It is estimated that PKD1 explains 85% and PKD2 15% of ADPKD cases. PKD2-related ADPKD is widely acknowledged to be of milder severity than PKD1-related disease.

The genomic region encompassing exons 1–33 of the PKD1 shares 90%–99% sequence homology with 6 known pseudogenes on chromosome 16, making this region very difficult to resolve using traditional NGS methods and resulting in reduced sensitivity to detect disease-causing variants.

Patient information

A 32-year-old female was diagnosed with bilateral renal cysts at 16 years of age.

Previous genetic testing

A next-generation sequencing (NGS) panel including PKD1 and PKD2 was negative.

Genetic testing

A Blueprint Genetics Polycystic Kidney Disease Panel was requested which tests for 10 genes including CNV analysis as well clinically relevant non-coding variants.

> Polycystic Kidney Disease Panel 

Diagnostic summary

Patient was heterozygous for PKD1 c.2534T>C, p.(Leu845Ser), which was classified as pathogenic. The variant was confirmed with bi-directional Sanger sequencing.

Diagnostic implications

Due to pseudogene interference involving exons 1-33 of PKD1, detection of disease-causing variants in this gene is challenging.

The clinical diagnosis in this patient is confirmed.

Blueprint Genetics’ Take Home

We offer a customized NGS based solution that provides exceptional coverage for the PKD1 and the ability to accurately map sequencing reads to the parent gene versus the pseudogenes.

> Read the full case report (PDF).