IFT80 was first reported in relation to autosomal recessive IFT80-related short-rib thoracic dysplasia (SRTD) in 2007 (Beales et al., PMID: 17468754). SRPS is characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern, with lethality dependent on the size of the thoracic cage being the primary difference in phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, short-rib thoracic dysplasia 2 with or without polydactyly (OMIM:611263), short-rib thoracic dysplasia (SRTD), asphyxiating throracid dystrophy (ATD), and Jeune syndrome. 16 variants (missense, in-frame indel, nonsense, frameshift, canonical splice site) that have been reported in 12 probands in 6 publications (PMIDs: 17468754, 19648123, 23339108, 29068549, 30767363, 33452237) are included in this curation. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by models replicating human phenotypes and ciliary alterations in Tetrahymena thermophila, zebrafish, and mice (PMIDs: 17468754, 17468754, 21227999). In summary, there is definitive evidence supporting the relationship between IFT80 and autosomal recessive IFT80-related short-rib thoracic dysplasia. 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 Skeletal Disorders GCEP on the meeting date August 5, 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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