PKHD1 – Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary hepatorenal fibrocystic disorder caused by biallelic mutations in the PKHD1 gene, encoding the ciliary protein fibrocystin/polyductin. Affected infants present with enlarged, echogenic kidneys, progressive renal insufficiency and congenital hepatic fibrosis. The condition follows an autosomal recessive inheritance pattern, with carrier frequency approximating 1:100 in some populations and an incidence of ~1:20,000 live births.

1. Clinical Validity

PKHD1 has a definitive gene–disease association with ARPKD, supported by over 500 unrelated probands (PMID:12506140), segregation of compound heterozygous or homozygous variants in multiple families, and concordant findings in animal and cellular models.

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation analyses have confirmed PKHD1 variants in >90 families, with compound heterozygous and homozygous LoF alleles co-segregating with disease. Case series report >500 probands carrying PKHD1 variants, including truncating, missense, splice and deep-intronic changes, with recurrence of hotspot alleles in population-specific cohorts. One representative variant is c.1626_1629del (p.Leu543fs).

3. Functional / Experimental Evidence

Loss-of-function is the primary mechanism: Pkhd1 knockout mice develop cystic kidneys and hepatic ductal plate malformations, mirroring human ARPKD (PMID:12191969). Patient-derived urine renal epithelial cells show aberrant splicing and ciliary defects, and tension modulation rescues epithelial polarity, underscoring fibrocystin’s role in adhesion and morphogenesis.

4. Conflicting Evidence

No studies have refuted the PKHD1–ARPKD link. Variable expressivity is observed but falls within the established phenotypic spectrum.

5. Integration & Clinical Utility

Extensive genetic and functional data establish PKHD1 as the definitive cause of ARPKD. Molecular testing enables prenatal and postnatal diagnosis, informs reproductive counseling, and supports clinical decision-making, including early intervention and family screening.

Key Take-home: PKHD1 biallelic mutations cause ARPKD via fibrocystin deficiency, with established diagnostic and prognostic utility in clinical practice.

References

• Nature genetics • 2002 • The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. PMID:11919560
• Journal of the American Society of Nephrology • 2003 • Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). PMID:12506140
• Journal of human genetics • 2019 • A rare deep intronic mutation of PKHD1 gene, c.8798-459 > A, causes autosomal recessive polycystic kidney disease by pseudoexon activation. PMID:30617278

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