UMOD was first reported in relation to autosomal dominant tubulointerstitial kidney disease (ADTKD) in 2002 (Hart et al., PMID 12471200). ADTKD due to UMOD pathogenic variants (ADTKD-UMOD) is diagnosed in individuals with a family history of chronic kidney disease leading to end stage kidney disease (ESKD), with little to no protein or blood in the urine. Hyperuricemia and gout may also be associated with family history. ADTKD-UMOD has been reported in the literature under the names familial juvenile hyperuricemic nephropathy type 1 and medullary cystic kidney disease type 2 (PMID 25738250). At least 125 unique variants (including missense, in-frame indel, and in-frame deletions) have been reported in humans with 97% of pathogenic variants clustering in exons 3 and 4 (PMID 32450155, PMID 32954071). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of Case Level Data: Variants in this gene have been reported in at least 19 individuals (PMID 12471200, PMID 12629136, PMID 12900848, PMID 1451790, PMID 14570709 PMID 32954071). Variants in this gene segregated with disease in 83 additional family members. The mechanism for disease is heterozygous toxic gain of function (PMID 14570709, PMID 16883323, PMID 28990932) with experimental evidence suggesting mutant UMOD is retained in the endoplasmic reticulum, the stress inducing the unfolded protein response (UPR), leading to tubular cell atrophy. Summary of Experimental Evidence: This gene-disease association is supported by expression studies in patient kidney biopsies, urine and serum, in vitro functional alteration studies, and mouse models (PMID 14570709, PMID 16883323, PMID 27729211, PMID 28990932, PMID 32926855, PMID 32954071). In summary, UMOD is definitively associated with autosomal dominant tubulointerstitial kidney disease. 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 Working Group on 01/13/2021 (SOP Version 8).
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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