WDR19 – Cranioectodermal Dysplasia

Cranioectodermal dysplasia (CED, Sensenbrenner syndrome) is an autosomal recessive ciliopathy characterized by a distinctive craniofacial gestalt, skeletal dysplasia, ectodermal anomalies and multiorgan involvement including hepatic fibrosis and chronic kidney disease. WDR19 encodes IFT144, a core WD‐repeat subunit of the IFT‐A complex essential for retrograde ciliary transport and structural integrity. Mutations in WDR19 disrupt ciliary assembly and signaling, underpinning the skeletal and craniofacial manifestations of CED.

Multiple independent families with biallelic WDR19 variants have been reported. Exome sequencing identified compound heterozygous WDR19 mutations in a Norwegian Sensenbrenner family and a homozygous missense allele in a Dutch pedigree with overlapping Jeune/CED features, and further cases in a French cohort (PMID:22019273, PMID:33606107). A separate study described a compound heterozygous CED patient carrying c.2129T>C (p.Leu710Ser) and a truncating allele (PMID:33517396). In total, at least six unrelated probands across four families support a recessive inheritance with segregation in multiple affected relatives ([PMID:22019273]).

The variant spectrum includes truncating (nonsense, frameshift, splice‐site) and hypomorphic missense alleles clustered in WD repeats. Functional hypomorphic alleles (e.g., c.2129T>C (p.Leu710Ser)) impair protein interactions within IFT‐A and partially rescue ciliogenesis, whereas truncating alleles abolish IFT144 function ([PMID:33517396]). No recurrent founder alleles have been described for CED.

Animal and cellular models corroborate pathogenicity. A mouse Ift144 hypomorphic/null allelic series phenocopies rib, limb and craniofacial defects of human CED and reveals dose‐dependent hedgehog dysregulation (PMID:22228095). In IFT144‐knockout cells, expression of mutant IFT144 alleles demonstrates allele‐specific effects on ciliogenesis and protein localization, faithfully modeling compound heterozygosity in patients ([PMID:33517396]). Evolutionary conservation is further highlighted by DYF‐2 studies in Caenorhabditis elegans (PMID:16957054).

No studies have refuted the WDR19–CED association, and the genetic and experimental data are concordant. Additional unpublished cohorts likely exist but exceed current ClinGen scoring limits.

Key take-home: Biallelic WDR19 variants cause autosomal recessive cranioectodermal dysplasia through disrupted IFT‐A–mediated ciliary transport, supporting genetic diagnosis, family counseling and potential future targeted therapies.

References

• American Journal of Human Genetics • 2011 • Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. PMID:22019273
• Child’s Nervous System • 2021 • Sensenbrenner syndrome: a further challenge in evaluating sagittal synostosis and a need for a multidisciplinary approach. PMID:33606107
• Human Molecular Genetics • 2021 • Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia. PMID:33517396
• Human Molecular Genetics • 2012 • Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies. PMID:22228095
• 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

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