The IFT27 gene is located in chromosome 22q12.3 and encodes the intraflagellar transport (IFT) 27 protein, a small GTPase within IFT complex-B. The protein has a regulatory role in the trafficking of proteins via the Bardet-Biedl Syndrome (BBS) complex (BBsome) into and out of cilia and it is also required for hedgehog signaling. It is ubiquitously expressed at varying levels in all tissues. IFT27 was first reported in relation to BBS in 2014 (Aldahmesh et al., PMID: 24488770). The mechanism of pathogenicity appears to be loss of function. Patients with biallelic IFT27 pathogenic variants presented with clinical features consistent with ciliopathies, including neurodevelopmental delay, retinitis pigmentosa, kidney disease, obesity, genital anomalies, and polydactyly.
At least 6 variants (missense, nonsense, frameshift, splice site) have been reported in five probands in five publications (PMIDs: 24488770, 29704304, 29588463, 30761183, 37239474) are included in this curation. The majority of the variants were loss of function. Functional data supports the pathogenicity of a missense variant and a splice site variant (PMIDs: 24488770, 30761183). A total of 7.1 pts. for genetic evidence was reached.
This gene-disease relationship is also supported by functional studies, expression studies, in vitro assays in non-patient cells, and animal models. Knockout zebrafish model showed typical ciliopathy phenotypes, like laterality defects, body curvature, and cystic kidneys (PMID: 24488770) and knockout mice displayed facial dysmorphism, abnormal palate development, spinal curvature, an abnormal rib cage, congenital heart disease, and various digit defects including polydactyly (PMID: 25446516). BBSome subunits and regulators cannot exit the cilia and instead accumulate in knockout mouse embryonic fibroblasts (PMID: 25446516, 25443296). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached.
In summary, there is definitive evidence supporting the relationship for IFT27 that we are terming autosomal recessive ciliopathy-IFT27. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel GCEP on the meeting date [February 10, 2025] (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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