IFT140 was first reported in relation to autosomal dominant polycystic kidney disease (ADPKD) in 2021 (Senum et al., PMID: 34890546). Biallelic IFT140 variants are causative in an autosomal recessive ciliopathy (OMIM: 266920), and have been curated as a separate gene-disease relationship. The proximity of IFT140 and PKD1 on chromosome 16 could lead to diagnostic confusion because of co-segregation in families and with PKD1 variants possibly modifying the IFT140 phenotype. However, there is strong evidence that IFT140, on its own, can cause kidney and liver cysts. More than 30 variants have been reported in individuals with renal cysts in 3 publications. Sixteen variants (nonsense, frameshift, and splice site) from 3 publications are included in this curation (PMIDs: 34890546, 37844724, 38404363). The distinctive monoallelic phenotype is a cystic kidney phenotype, of ranging severity, with large cysts, usually preserved kidney function, varying prevalence of hypertension, and, in some cases, liver cysts. Chronic kidney disease is usually mild and does not progress to end-stage kidney disease. This gene-disease relationship has been studied in 1 case-control study (Senum et al.) at the aggregate variant level with an OR of 12.81. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, in the form of a mouse model (Jonassen et al., PMID: 22282595). This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic & Ciliopathy GCEP on 4/15/2022. It was re-evaluated on 3/11/2024. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of genetic evidence (PMIDs: 37844724, 38404363). In summary, there is Definitive evidence supporting the relationship between IFT140 and an autosomal dominant kidney cystic phenotype. 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 & Ciliopathy Gene Curation Expert Panel (GCEP) on the meeting date 3/11/24 (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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