IFT52 and Cranioectodermal Dysplasia

IFT52 has emerged as a key gene implicated in the pathogenesis of cranioectodermal dysplasia, a rare autosomal recessive ciliopathy. Multiple independent studies have identified biallelic, pathogenic variants in IFT52 among affected individuals, thereby strengthening the gene‐disease association. In particular, literature indicates that over 70 cases associated with cranioectodermal dysplasia have been reported, with IFT52 being one of the contributory genes (PMID:35281231). The identification of diverse variant classes, including missense and loss‑of‑function mutations, underscores the broad spectrum of genetic alterations observed in this condition.

The genetic evidence is further supported by segregation data and variant analyses. Detailed assessment of reported cases reveals that pathogenic variants in IFT52, such as the nonsense change c.424C>T (p.Arg142Ter), are observed in unrelated probands and demonstrate co‐segregation with disease phenotypes, although extended segregation information remains limited. This variant, which is predicted to result in premature truncation and loss of function, exemplifies the molecular defects contributing to the disorder (PMID:31042281).

Cranioectodermal dysplasia resulting from IFT52 mutations follows an autosomal recessive inheritance pattern. Although the number of additional affected relatives with confirmed segregating variants is minimal, the recurrent identification of pathogenic alleles across independent families bolsters the clinical relevance of these findings. The genetic data, when viewed in aggregate, fulfill key criteria for a strong gene‑disease association under ClinGen guidelines.

Functional studies provide critical experimental confirmation of the pathogenic role of IFT52 mutations. In vitro analyses and in vivo zebrafish models have demonstrated that loss of IFT52 function disrupts the assembly of the IFT‑B complex, interferes with cilia elongation, and perturbs microtubule dynamics and centrosome cohesion. These cellular defects are consistent with the phenotypic manifestations observed in cranioectodermal dysplasia, thereby linking the molecular alterations directly to disease pathogenesis (PMID:30242358; PMID:31042281).

Integrating the genetic and functional evidence, a coherent narrative emerges that underscores the crucial role of IFT52 in normal ciliary biology and its perturbation in cranioectodermal dysplasia. The robust identification of multiple disruptive mutations in IFT52 from independent cohorts, combined with functional data from model systems, supports a strong ClinGen category for this gene‑disease relationship. This integrated approach highlights the utility of IFT52 variant screening for diagnostic decision‑making in patients with clinical features of cranioectodermal dysplasia.

In summary, the extensive genetic and experimental evidence justifies a strong association between IFT52 and cranioectodermal dysplasia. Clinicians and diagnostic laboratories should consider comprehensive variant analysis of IFT52 as part of the evaluation for ciliopathy patients, thus enhancing diagnostic precision and guiding subsequent clinical management.

References

• Human Molecular Genetics • 2019 • Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion PMID:31042281
• Frontiers in Pediatrics • 2022 • Case Report: Sequential Liver After Kidney Transplantation in a Patient With Sensenbrenner Syndrome (Cranioectodermal Dysplasia) PMID:35281231
• Investigative Ophthalmology & Visual Science • 2018 • IFT52 as a Novel Candidate for Ciliopathies Involving Retinal Degeneration PMID:30242358

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