WDR35 – Cranioectodermal Dysplasia (Sensenbrenner Syndrome)

Cranioectodermal dysplasia (CED), or Sensenbrenner syndrome, is a rare autosomal recessive ciliopathy characterized by craniofacial dysmorphism, skeletal anomalies, ectodermal defects, and progressive renal and hepatic involvement. WDR35 (HGNC:29250) encodes IFT121, a component of the IFT-A complex required for primary and, as recently shown, motile ciliogenesis. Biallelic WDR35 mutations were first identified by exome sequencing in two unrelated CED patients, confirming WDR35 as a CED-causing gene (PMID:20817137). Subsequent studies have reported over 50 patients from more than 20 unrelated families harboring compound heterozygous or homozygous WDR35 variants, underscoring the gene’s central role in CED pathogenesis (PMID:24123776).

Genetic evidence supports autosomal recessive inheritance with segregation of WDR35 variants in multiple affected sibships. At least 30 probands have been described carrying compound heterozygous or homozygous changes in WDR35, with two or more affected siblings in several families demonstrating co-segregation of variants with disease (PMID:28332779). Segregation analysis in a Polish cohort showed two additional affected relatives carrying the same compound heterozygous alleles, reinforcing pathogenicity.

The WDR35 variant spectrum includes missense (e.g., c.206G>A (p.Gly69Asp)), nonsense (e.g., c.1922T>G (p.Leu641Ter)), splice-site (e.g., c.1288+1G>A), and frameshift (e.g., c.3009del (p.Leu1004fs)) alleles. Recurrent variants such as c.1922T>G (p.Leu641Ter) and c.2522A>T (p.Asp841Val) have been observed in multiple Polish families, suggesting possible founder effects (PMID:28332779).

Functional studies demonstrate that WDR35 deficiency disrupts ciliogenesis and ciliary structure across cell types. siRNA-mediated knockdown of WDR35 in human airway epithelia caused failure of motile cilia assembly, linking WDR35 loss to mucociliary clearance defects (PMID:25914204). In urine-derived renal epithelial cells from a CED patient, WDR35 variants led to abnormally long and wide primary cilia, correlating with CKD progression in CED (PMID:38161384).

No significant conflicting gene-disease associations have been reported. The concordance of genetic segregation, robust functional assays, and consistent phenotypes across independent cohorts supports a Strong clinico-genetic validity for WDR35 in cranioectodermal dysplasia. Genetic evidence reaches a Strong tier given segregation in multiple families and diverse pathogenic variants, while functional evidence is Moderate based on cellular knockdown and phenotyping studies.

Key Take-Home: Biallelic WDR35 mutations cause autosomal recessive cranioectodermal dysplasia through impaired intraflagellar transport leading to defective ciliogenesis; genetic testing of WDR35 is recommended in CED diagnostic panels to guide clinical management and family counseling.

References

• American Journal of Human Genetics • 2010 • Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome PMID:20817137
• American Journal of Medical Genetics Part A • 2013 • Sensenbrenner syndrome (Cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients PMID:24123776
• American Journal of Medical Genetics Part A • 2015 • Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia PMID:25914204
• American Journal of Medical Genetics Part A • 2017 • Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations PMID:28332779
• Frontiers in Molecular Biosciences • 2023 • Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with WDR35 variants PMID:38161384

Evidence Based Scoring (AI generated)