Submission Details

IFT172 was first reported in relation to autosomal recessive ciliopathy in 2013 by Halbritter et al. (PMID: 24140113). This condition includes abnormal cilia, skeletal anomalies (such as polydactyly and thoracic dystrophy), kidney features (such as end-stage renal disease and kidney cysts), and vision issues (including retinal dystrophy). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no differences in inheritance patterns, and the range of symptoms was more reflective of a spectrum than of distinct conditions. Therefore, the following disease entities have been lumped into one disease entity: autosomal recessive Bardet-Biedl syndrome (OMIM: 619471); autosomal recessive short-rib thoracic dysplasia with or without polydactyly (OMIM: 615630), and autosomal recessive retinitis pigmentosa (OMIM: 616394). 18 variants (missense, in-frame deletion, nonsense, frameshift, splicing) that have been reported in at least 14 probands in 5 publications (PMIDs: 24140113, 25492405, 33393400, 34567078, 37471416) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (zebrafish model, interaction evidence; PMIDs: 21552265, 24140113). Morpholino knockdown zebrafish exhibit abnormal ciliogenesis, cartilage anomalies, kidney cysts, and hydrocephalus. Expression of IFT172 was shown to reduce lethality and penetrance of polydactyly in DYNC2H1 homozygous mutants, showing genetic interaction. In summary, there is definitive evidence supporting the relationship between IFT172 and autosomal recessive ciliopathy-IFT172. 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 the meeting date 04/23/2025 (SOP Version 11).