The IFT74 gene has been identified as involved in the function and growth of cilia, specifically facilitating tubulin transport into cilia as part of a complex with IFT81 (PMID:37315079, 37555648). Variants in the IFT74 gene have been reported in individuals with a variety of ciliopathy phenotypes including Joubert syndrome, Bardet-Biedl Syndrome, Jeune Asphyxiating Thoracic Dystrophy, Short Rib Polydactyly and nonsyndromic infertility. Primary Ciliary Dyskinesia (PCD) is a condition of impaired ciliary function characterized by neonates with respiratory distress, recurrent chest infections and cough. In about half of the individuals with PCD, situs abnormalities have been described. Given the overlap with IFT74 function and PCD, as well as the reported presence of variants in patients with PCD-like phenotypes, this gene was evaluated for gene-disease association with PCD. At the time of this review, individuals with phenotypes consistent with PCD (i.e. recurrent sinusitis, recurrent respiratory infection, otitis media, neonatal respiratory distress, reduced/shortened cilia, low nNO measurements) were identified in 2 case series. All of these individuals have a homozygous deletion of exon 2. For this gene, exon 2 represents the first coding exon. Of note, all individuals presenting with this phenotype were also clinically diagnosed with Jeune Asphyxiating Thoracic Dystrophy. At the time of this review, no individuals presenting with PCD in isolation have been identified in the literature. Variant specific functional studies utilizing Western blot identified abnormal banding as compared to wild type in these individuals (PMID:37315079, 37555648).
Experimental evidence supporting this gene-disease relationship includes knockdown assays in zebrafish models that express cilia abnormalities (i.e. severe ventral body curvature) and mouse models that express cilia abnormalities (cardiac malformations, polydactyly, hydrocephalus, abnormal cilia) that can be rescued with wild-type IFT74 (PMID: 33531668, 37315079).
In summary, IFT74 has a Limited association to Primary Ciliary Dyskinesia based on genetic and experimental evidence data points. This classification was approved by the ClinGen Motile Ciliopathy GCEP on 1/9/25 (SOP Version 11).
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