中国ARPKD家系における新規複合ヘテロ接合型PKHD1変異と同定された遺伝子型-表現型相関の解析

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited renal disorder characterized by multiple renal cysts. This study aimed to investigate the pathogenesis of PKHD1 gene variants in a Chinese ARPKD pedigree and elucidate the mechanisms underlying the phenotypic heterogeneity in patients with PKHD1 mutations.

Clinical data and blood samples were collected from the proband and family members. Whole-exome sequencing (WES) and Sanger sequencing were performed. Conservative analysis and local secondary structure prediction of the mutation site were performed to evaluate the pathogenicity. The genotype-phenotype correlation of PKHD1 mutations was analyzed in combination with this pedigree.

A pediatric patient with ARPKD was identified. Ultrasonography revealed bilateral renal enlargement with multiple cysts, accompanied by hepatic fibrosis. WES identified a novel compound heterozygous variant in the PKHD1 gene (c.5850_5851insTTCAT; p.Gly1951Phefs*25 and c.8710G > A; p.Glu2904Lys). Conservation analysis confirmed that both mutations occurred in conserved regions, indicating potential pathogenicity. Secondary structure prediction revealed that the p.Gly1951Phefs*25 frameshift mutation resulted in protein truncation and conformational changes, whereas the p.Glu2904Lys missense mutation caused drastic changes in amino acid polarity, impairing protein stability and function. Genotype-phenotype analysis of 605 PKHD1 mutations revealed a trend suggesting that hepatobiliary manifestations might present with less severe mutational burden compared to renal phenotypes, and mild homozygous missense mutations or heterozygous states may attenuate or eliminate renal phenotypes.

This study uncovered novel PKHD1 mutations in an ARPKD patient, expanding the pathogenic gene spectrum of ARPKD and providing insights for genetic counseling and prenatal diagnosis. Our findings also contribute to the understanding of genotype-phenotype correlations in PKHD1 mutation carriers and generate hypotheses regarding potential organ-specific thresholds for disease manifestation.