WDR19 – Broad Spectrum Ciliopathy

Primary cilia dysfunction underlies a spectrum of autosomal recessive ciliopathies characterized by renal, hepatic, skeletal, neurologic, and retinal involvement. Biallelic WDR19 variants disrupt intraflagellar transport component IFT144, leading to phenotypes ranging from nephronophthisis and Caroli disease to retinitis pigmentosa and Stargardt-like degeneration. Genetic segregation in two sibships and consistent functional assays support a robust gene–disease link.

Clinical Validity

Multiple unrelated probands (n = 13) across at least seven families (PMID:24504730; PMID:35362211; PMID:40183892; PMID:25726036; PMID:32323121) and segregation in two sibships (PMID:25726036; PMID:40183892) establish a Strong association. Consistent concordance between human phenotypes and animal/cellular models further fortifies this classification.

Genetic Evidence

Inheritance is autosomal recessive. Case series include an index child with homozygous c.1483G>C (p.Gly495Arg) (PMID:24504730), a second subject with compound heterozygous c.742G>A (p.Gly248Ser) and c.617T>C (p.Leu206Pro) (PMID:35362211), four individuals from three families with diverse retinal degeneration genotypes (PMID:40183892), and six Korean patients harboring recurrent p.Arg1178Gln and other biallelic variants (PMID:25726036). Variant spectrum comprises missense, splice-site, and frameshift alleles, including a recurrent founder p.Arg1178Gln in East Asians.

Functional Evidence

Evolutionarily conserved IFT144 orthologues in Caenorhabditis elegans and mouse demonstrate that loss of DYF-2/WDR19 impairs ciliary assembly, motility, and hedgehog signaling (PMID:16957054; PMID:22228095). Patient kidney immunohistochemistry reveals altered WDR19 localization in renal tubular epithelium (PMID:25726036). Collectively, these data support a loss-of-function mechanism.

Integration and Clinical Utility

Biallelic WDR19 variants consistently yield a pleiotropic ciliopathy phenotype encompassing kidney failure, hepatic fibrosis, skeletal dysplasia, neurologic impairment, and retinal degeneration. Genetic testing panels for ciliopathies should include WDR19, and detection of pathogenic variants informs prognosis, family counseling, and potential eligibility for emerging cilia-targeted therapies.

Key Take-home: Autosomal recessive WDR19 loss-of-function variants cause a clinically and genetically validated broad spectrum ciliopathy, guiding diagnostic and therapeutic strategies.

References

• Pediatric nephrology • 2014 • Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies. PMID:24504730
• American journal of medical genetics. Part A • 2022 • A unique pancreatic phenotype in a child with a WDR19-related ciliopathy: A case report and literature review of pancreatic involvement in ciliopathies PMID:35362211
• Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney • Pediatric nephrology • 2015 • Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney PMID:25726036
• A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia • Journal of assisted reproduction and genetics • 2020 • A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia PMID:32323121
• Phenotypic spectrum and theoretical prime editing analysis of WDR19-mediated retinal degeneration • Documenta ophthalmologica. Advances in ophthalmology • 2025 • Phenotypic spectrum and theoretical prime editing analysis of WDR19-mediated retinal degeneration PMID:40183892
• Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia • Molecular biology of the cell • 2006 • Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia PMID:16957054
• Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies • Human molecular genetics • 2012 • Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies PMID:22228095

Evidence Based Scoring (AI generated)