TRAF3IP1 (OMIM: 607380), located at 2q37.3, encodes the intraflagellar transport protein IFT54, a subunit of the IFT-B complex essential for ciliogenesis and anterograde ciliary transport (PMIDs: 26487268, 21945076, 33368450). Autosomal recessive pathogenic variants in TRAF3IP1 are associated with Senior-Loken Syndrome 9 (OMIM: 616629) and broader ciliopathies, including Short-Rib Polydactyly Syndrome Type II (MONDO:0005308). Based on the ClinGen Lumping and Splitting Working Group criteria, these entities were classified under "autosomal recessive ciliopathies" due to shared molecular mechanisms, inheritance patterns, and overlapping phenotypes. The mechanism is biallelic loss-of-function, resulting in ciliary defects presenting as syndromic ciliopathies, including nephronophthisis, retinal degeneration, and skeletal or hepatic abnormalities.
At least 10 TRAF3IP1 variants, including protein-truncating and missense mutations, have been reported in the literature, associated with ciliopathy phenotypes such as nephronophthisis, retinal degeneration, and polydactyly (PMIDs: 26487268, 29068549). Segregation and functional studies confirm that loss-of-function is the primary pathogenic mechanism. Functional evidence demonstrates impaired ciliary trafficking and microtubule stability caused by these variants (PMID: 26487268). Traf3ip1-knockout mouse embryos recapitulate lethal ciliopathy-related phenotypes due to disrupted ciliogenesis, cell size regulation, and Sonic Hedgehog signaling (PMID: 21945076). Furthermore, wild-type TRAF3IP1 mRNA partially rescues ciliopathy-associated phenotypes in zebrafish, such as body axis curvature, pronephric cysts, and retinal degeneration, whereas patient-specific constructs fail to rescue these defects (PMID: 26487268).This gene-disease relationship is supported by comprehensive genetic evidence (10.2/12 points) and experimental evidence (6/6 points).
In summary, there is definitive evidence supporting the relationship between TRAF3IP1 and autosomal recessive ciliopathies. 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 GCEP on 11/27/2024 (SOP Version 10).
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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