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IFT43 (HGNC:29669) has been implicated in autosomal recessive cranioectodermal dysplasia (Sensenbrenner syndrome) (MONDO:0009032), characterized by craniofacial dysmorphism, skeletal anomalies, chronic renal failure, cardiac defects, and hepatic fibrosis. Homozygosity mapping in a consanguineous Moroccan family identified a homozygous initiation codon variant, c.1A>C (p.Met1Leu), in two affected siblings (PMID:21378380). No additional unrelated families with IFT43 pathogenic variants have been reported. Inheritance follows an autosomal recessive pattern with affected relatives limited to these siblings.
Functional analyses demonstrated that the c.1A>C variant abolishes the canonical start codon, leading to translation of a truncated IFT43 protein as shown by western blot in patient fibroblasts. Ciliary assays revealed impaired IFT-A–mediated retrograde transport with accumulation of IFT-B proteins at the ciliary tip, while anterograde transport remained intact (PMID:21378380). These findings mirror defects seen in other IFT-A subunit deficiencies and support a loss-of-function mechanism. Biallelic loss-of-function in IFT43 provides diagnostic confirmation of CED, guiding multidisciplinary management of renal, hepatic, and cardiac complications.
Key Take-home: Biallelic LoF variants in IFT43 cause cranioectodermal dysplasia via disrupted retrograde ciliary transport, underscoring the gene’s clinical utility in diagnostics.
Gene–Disease AssociationLimitedTwo probands in a single consanguineous family; no additional unrelated cases reported Genetic EvidenceLimitedHomozygous initiation codon variant in two siblings (AR), no further segregation Functional EvidenceModerateWestern blot and ciliary transport assays demonstrate truncated IFT43 and retrograde transport defect |