Submission Details

REN was FIRST reported in relation to autosomal dominant tubulointerstitial kidney (ADTKD; OMIM: 613092) in 2009 (Zivna et al, PMID: 19664745). ADTKD-REN is characterized by a family history of chronic kidney disease, childhood anemia (if the mutation is located in the signal peptide or prosegment of renin), hyperuricemia (in 60% of cases), mild hyperkalemia, bland urinary sediment and slowly progressive chronic kidney disease, leading to end-stage kidney disease (ESKD) at between 30 – 80 years of age (PMIDs: 32750457, 19664745, 21084044, 21903317, 28701203, 31406136, 31586593). The REN gene is associated with two disease entities by different pattern of inheritance and molecular mechanisms as well as different clinical findings including: (1) Autosomal dominant tubulointerstitial kidney disease (ADTKD-REN; OMIM: 613092) and (2) Renal tubular dysgenesis (RTD; OMIM: 267430). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these two disease entities have been curated separately. Variants in REN have been reported in at least 120 individuals (from more than 30 families) and segregated with the disease (PMIDs: 19664745, 32750457, 21084044, 21903317, 28701203, 31406136, 31586593). At least 15 unique variants (including in-frame deletion and missense variants) have been reported. Renin is synthesized as pre-pro-renin consisting of a signal peptide (pre), prosegment (pro) and mature part of renin. More than 60% of cases are caused by mutations in the signal peptide, 25% of mutations are in the prosegment and 15% are in the mature part renin. The mechanism of the disease depends on the mutated domain. Mutations in the signal peptide result in synthesis of a preprorenin that is not processed and is aberrantly located in the cytoplasm. Mutations in the prosegment introduce structural changes affecting protein biosynthesis, folding, and transport along the secretory pathway. Mutations in mature renin lead to retention of the mutated protein in the endoplasmic reticulum. All of these molecular mechanisms result in ER stress activation and cellular toxicity to renin-producing cells, leading to apoptosis, clinical renin deficiency and chronic kidney disease. ADTKD-REN patients have hyporeninemic hypoaldosteronism, which can be treated with administration of the synthetic aldosterone analog fludrocortisone (PMIDs: 21084044, 21473025). This gene-disease association is supported by immunohistochemical studies of renin in patient kidney biopsies, determination of plasma renin levels, experimental cellular models (PMIDs: 19664745, 32750457) and a zebrafish model (PMID: 31406136). In summary, there is DEFINITIVE evidence to support the relationship between REN and autosomal dominant tubulointerstitial kidney disease (ADTKD-REN). 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 10/28/2020 (SOP Version 7).