Next-Generation Sequencing Defines a Molecularly Confirmed ARPKD Core Within the Broader PKHD1-Associated Disease...

Area of Science:

• Genetics
• Pediatric Nephrology
• Medical Genomics

Background:

• Autosomal recessive polycystic kidney disease (ARPKD) is a severe ciliopathy linked to PKHD1 gene variants.
• Next-generation sequencing (NGS) has identified numerous rare PKHD1 variants, complicating ARPKD diagnosis.
• Distinguishing molecularly confirmed ARPKD from broader PKHD1-associated diseases is challenging.

Purpose of the Study:

• To integrate clinical and molecular data for precise ARPKD diagnosis.
• To stratify patients based on PKHD1 variant pathogenicity and zygosity.
• To establish genotype-phenotype correlations in molecularly confirmed ARPKD.

Main Methods:

• Performed integrated clinical and molecular analysis of 68 individuals with suspected ARPKD.
• Utilized phase-aware and family-informed ACMG classification for variant interpretation.
• Stratified patients into confirmed ARPKD, uncertain pathogenicity, and carrier groups.

Main Results:

• 40 patients had molecularly confirmed ARPKD, with varying loss-of-function (LoF) allele burdens.
• A significant allele-dose effect was observed for renal disease onset and progression to renal replacement therapy.
• Hepatic disease prevalence was high across all genotype groups and not significantly associated with LoF burden.

Conclusions:

• Phase-aware interpretation of PKHD1 variants accurately defines the ARPKD core.
• LoF allele burden is the key determinant of renal and perinatal severity in ARPKD.
• Hepatic involvement in ARPKD is largely independent of truncating allele burden, aiding prognosis and genetic counseling.