WDR19 – Senior-Loken Syndrome

Senior-Loken syndrome (SLSN) is an autosomal recessive ciliopathy defined by the combination of retinal degeneration and juvenile‐onset nephronophthisis. Patients present early with impaired vision, nystagmus and progressive renal fibrosis leading to end‐stage kidney disease.

Genetic evidence for WDR19 in SLSN arises from a retrospective series of 74 unrelated families, in which biallelic WDR19 variants accounted for 2.9% of cases (2 probands) (PMID:36990420). All affected individuals harbored two rare missense or splice‐site variants consistent with autosomal recessive inheritance and absence of nephronophthisis in heterozygous carriers.

The variant spectrum includes both canonical splice-site disruptions (e.g., c.98+1G>C) and recurrent missense changes such as c.3533G>A (p.Arg1178Gln), originally reported in nephronophthisis‐13 and Caroli disease (PMID:25726036). These variants are predicted to impair WDR19 function via aberrant pre-mRNA processing or disruption of WD repeats critical for intraflagellar transport (IFT).

Functional studies in model systems demonstrate that WDR19 (IFT144) is a core component of the IFT-A complex: loss of DYF-2 (the C. elegans orthologue) impairs IFT particle assembly and cilia formation (PMID:16957054), while renal immunohistochemistry of patient biopsies shows mislocalized WDR19 in tubular epithelium (PMID:25726036). Mouse IFT144 hypomorphic alleles phenocopy human ciliopathies, confirming a dose-dependent requirement of WDR19 in ciliogenesis and organ development (PMID:22228095).

No studies to date have refuted the association or described phenotypes discordant with SLSN. The combined genetic and experimental data support a loss-of-function mechanism for WDR19 in SLSN pathogenesis.

Taken together, biallelic WDR19 variants meet ClinGen moderate clinical validity for Senior-Loken syndrome. Further large‐scale screening and segregation analyses will solidify penetrance estimates and guide carrier testing.

Key Take‐home: Biallelic WDR19 variants cause autosomal recessive Senior-Loken syndrome through disrupted IFT-A–mediated ciliogenesis, supporting its use in diagnostic panels for early retinal and renal ciliopathies.

References

• Journal Unknown • ____ • Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis; this study aimed to evaluate whether different phenotypes are associated with different variants in 10 SLSN genes based on an in-house data set and a literature review. PMID:36990420
• Pediatric nephrology (Berlin, Germany) • 2015 • Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney. PMID:25726036
• 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
• Human molecular genetics • 2012 • Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies. PMID:22228095

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