Abstract
ABSTRACT
Aim
Primary hyperoxaluria (PH) represents a rare genetic disorder characterised by incompletely elucidated causative genes and limited therapeutic options. This study aims to identify PH‐associated genetic variants and potential drug targets.
Methods
We performed exon sequencing of eight PH patients to find PH‐related mutant genes, and used the PH rat model to explore differentially expressed genes related to PH. Key core genes related to PH are identified through functional enrichment analysis and protein interaction analysis.
Results
Whole‐exome sequencing of eight patients with a clinical diagnosis of Primary Hyperoxaluria Type 1 (PH1) identified biallelic pathogenic or likely pathogenic
AGXT
variants in five individuals. One patient was partially confirmed, and two patients were clinically confirmed only. Additional rare variants were detected across
AGXT
,
GRHPR
,
HOGA1
,
PEX1
and
OxGR1
; variants in intronic regions were retained only if predicted to affect splicing. In total, two patients harboured ≥ 20 rare variants in
AGXT
, and four patients had > 10 rare variants in
PEX1
. Across five candidate genes, 548 shared variant‐bearing genes were enriched in cytoskeletal organization and cell adhesion. SNV analysis showed frameshift insertions and deletions as the most frequent mutation types, and
AGAP3
and SON were the most heavily mutated, implicating NK cell regulation. Germline rare variant load—defined as the total number of rare variants (MAF
Conclusion
This study provides new insights into PH pathogenesis through integrative WES and transcriptomic analysis, identifying hypothesis‐generating candidate genes potentially linked to nephrolithiasis susceptibility in this small cohort that warrant further functional validation in larger, independent populations.