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IFT172 has been robustly associated with Bardet-Biedl syndrome, a recessive ciliopathy characterized by rod‑cone dystrophy, obesity, postaxial polydactyly, cognitive impairment, and hypogonadism. Multiple independent studies have identified variants in IFT172 with segregation in affected families, supporting its role as a causative gene in this disorder (PMID:26763875).
Genetic evidence includes the identification of a homozygous splice‑site variant in a consanguineous family, along with reports of additional missense, nonsense, and splice‑site alterations in unrelated probands. In one key study, a critical variant, c.296G>A (p.Trp99Ter), was reported, and its presence across independent case series reinforces the genetic association (PMID:25168386). Segregation analysis in affected relatives further supports an autosomal recessive mode of inheritance (PMID:32451492).
Functional studies, including cell‐based assays and animal models, have demonstrated that IFT172 mutations disrupt intraflagellar transport, a process essential for the formation and maintenance of primary cilia. These defects are consistent with the multisystem clinical findings observed in Bardet-Biedl syndrome, linking molecular dysfunction with the human phenotype (PMID:25168386).
Additional experimental work has extended these findings by showing that perturbations in ciliary assembly due to IFT172 insufficiency can lead to a spectrum of phenotypes ranging from isolated retinal degeneration to full‐blown Bardet‑Biedl syndrome. The convergence of genetic and functional data has, therefore, established a strong evidence base for the role of IFT172 in the pathogenesis of this ciliopathy.
Despite some variability in the clinical presentation, the cumulative data from case reports, segregation studies, and functional assays exceed the minimum criteria for a strong gene‑disease relationship. This association not only aids in diagnostic decision‑making but also supports the importance of IFT172 as a target for future therapeutic research and commercial genetic testing applications.
Key Take‑home: The strong genetic and functional evidence linking IFT172 mutations to Bardet-Biedl syndrome confirms its clinical utility as a diagnostic marker and potential therapeutic target.
Gene–Disease AssociationStrongMultiple independent studies demonstrating pathogenic variants in IFT172 in unrelated probands with Bardet-Biedl syndrome (PMID:26763875, PMID:32451492) and supported by concordant functional evidence (PMID:25168386). Genetic EvidenceStrongThe detection of diverse variant classes, including the key variant c.296G>A (p.Trp99Ter), in multiple families and the demonstration of segregation with disease in an autosomal recessive pattern reinforce the genetic contribution of IFT172. Functional EvidenceModerateFunctional assays have confirmed that IFT172 mutations impair ciliary transport, a mechanism that aligns with the clinical spectrum observed in Bardet-Biedl syndrome, although variability in model systems warrants further validation. |