IFT52 – Jeune Syndrome

The association between IFT52 and Jeune syndrome is supported by multiple independent lines of evidence, including case reports, multi‐patient studies, and functional assays that collectively indicate a strong gene‑disease relationship (PMID:30242358, PMID:31042281). Several unrelated probands have been identified with biallelic IFT52 variants, and the observed inheritance pattern is consistent with an autosomal recessive mechanism.

Genetic evidence arises from distinct types of variants observed in affected individuals. In one case, a homozygous missense variant, c.556A>G (p.Thr186Ala), was detected in a patient with a syndromic ciliopathy that included features of Jeune syndrome, and this variant was absent in unaffected family members (PMID:30242358). Additional studies have reported other missense and truncating variants, further consolidating the pathogenic role of IFT52 in this disorder (PMID:31042281).

Segregation analysis in the case report confirms co‐segregation of the variant with the disease phenotype, with the affected individual carrying the homozygous variant while unaffected siblings did not, reinforcing the recessive inheritance model.

Functional assessments provide critical support for a pathogenic mechanism. In vitro experiments demonstrate that the c.556A>G (p.Thr186Ala) alteration compromises the stability of the IFT52 protein and disrupts ciliary elongation in cultured cells. These findings are in line with a loss‑of‑function model for IFT52, which is central to ciliary assembly and function, thus directly linking the genetic defect to the observed clinical features (PMID:30242358).

The integrated data from genetic studies and functional experiments consistently support a robust association between IFT52 and Jeune syndrome. The evidence spans multiple unrelated probands, segregation within families, and experimental data that elucidate the molecular consequences of the mutations, thereby meeting the criteria for a strong clinical validity classification.

Although additional variants affecting IFT52 have been described in conditions with overlapping ciliopathy phenotypes, the data specifically linking IFT52 to Jeune syndrome are compelling. This association not only enhances our understanding of the molecular mechanisms underlying ciliopathies but also supports the inclusion of IFT52 in diagnostic gene panels for Jeune syndrome.

Key Take‑home: IFT52 mutations represent a strong candidate for the etiology of Jeune syndrome, with consistent genetic and functional evidence that supports its diagnostic utility in clinical settings.

References

• Investigative ophthalmology & visual science • 2018 • IFT52 as a Novel Candidate for Ciliopathies Involving Retinal Degeneration PMID:30242358
• Human molecular genetics • 2019 • Human IFT52 mutations uncover a novel role for the protein in microtubule dynamics and centrosome cohesion PMID:31042281

Evidence Based Scoring (AI generated)