PKHD1 – Caroli disease

Autosomal recessive Caroli disease is characterized by cystic dilatation of the intrahepatic bile ducts and is caused by pathogenic variants in PKHD1. Multiple independent studies have identified biallelic PKHD1 variants in families and sporadic cases presenting with Caroli disease or Caroli syndrome, supporting a causal relationship.

Clinical Validity

PKHD1–Caroli disease association is classified as Moderate based on PKHD1 variants reported in 7 probands across 3 families with clear cosegregation and absence in controls, and concordant phenotypes in intrahepatic bile duct malformations. 2 probands in a twin family ([PMID:24710345]) and 3 affected siblings in a ductal plate malformation cohort ([PMID:26385851]) show recessive inheritance and co-segregation of compound heterozygous alleles.

Genetic Evidence

Inheritance mode: Autosomal recessive. Segregation: 5 affected relatives with PKHD1 variants in two multiplex families. Case series include compound heterozygous missense and nonsense alleles such as c.2341C>T (p.Arg781Ter) and c.2507T>C (p.Val836Ala) in twins ([PMID:24710345]), and c.10444C>T (p.Arg3482Cys) with c.5521G>A (p.Glu1841Lys) in siblings ([PMID:26385851]). Singleton adult cases with c.370C>T (p.Arg124Ter) & c.4870C>T (p.Arg1624Trp) ([PMID:30984525]) and c.1877A>G (p.Lys626Arg) ([PMID:28814334]) further expand the spectrum. Most pathogenic alleles are truncating or hypomorphic missense, consistent with loss‐of‐function mechanism.

Functional Evidence

PKHD1 expression is high in renal and biliary tubular structures in mouse (Pkhd1) and human tissues, supporting a role in ductal plate morphogenesis ([PMID:12191969]). Murine orthologue knock‐out models recapitulate biliary and renal cystogenesis, indicating that fibrocystin deficiency disrupts bile duct architecture and promotes cystic dilatation.

Integration and Conclusion

Genetic and experimental data converge on a loss‐of‐function mechanism for PKHD1 in Caroli disease, with biallelic truncating or hypomorphic variants causing ductal plate malformations. While additional large cohorts and functional assays of individual variants would strengthen evidence, current data support PKHD1 testing in suspected Caroli disease for diagnostic and counseling applications.

Key take-home: PKHD1 should be included in genetic testing panels for autosomal recessive Caroli disease, as biallelic loss‐of‐function variants reliably predict cystic biliary pathology.

References

• PLoS one • 2014 • Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease. PMID:24710345
• American journal of medical genetics. Part A • 2015 • Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations. PMID:26385851
• Balkan journal of medical genetics : BJMG • 2018 • The Role of Next Generation Sequencing in the Differential Diagnosis of Caroli's Syndrome. PMID:30984525
• Diagnostic pathology • 2017 • Abernethy malformation associated with Caroli's syndrome in a patient with a PKHD1 mutation: a case report. PMID:28814334
• Journal of the American Society of Nephrology : JASN • 2002 • Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene. PMID:12191969

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