Submission Details

REN was FIRST reported in relation to autosomal recessive renal tubular dysgenesis (RTD; OMIM: 267430) in 2005 (Gribouval et al, PMID: 16116425). RTD is characterized by prenatal development with hypoperfusion during fetal development leading to abnormal kidney development, persistent anuria, persistent oligohydramnios that leads to the Potter sequence (clubbed feet, pulmonary hypoplasia and cranial anomalies), skull ossification defects and perinatal death. The histopathological hallmark of the disease is absence or poor development of proximal tubules and glomeruli. Approximately 20% of RTD cases are caused by either homozygous or compound heterozygous mutations in REN. Other known cases of RTD are associated with biallelic mutations in genes encoding other components of the renin-angiotensin system (RAS, e.g. angiotensin and angiotensin converting enzyme). The REN gene is associated with two disease entities by different inheritance patterns and molecular mechanisms, as well as different clinical findings including: (1) renal tubular dysgenesis (RTD-REN; OMIM: 267430) and (2) autosomal dominant tubulointerstitial kidney disease (ADTKD-REN; OMIM: 613092). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these two disease entities have been curated separately.

Variants in the REN gene have been reported in at least 20 individuals (PMIDs: 16116425, 22095942, 17443344, 27994858). Homozygous or compound heterozygous variants in this gene segregated with the disease. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is loss of function. Biallelic nonsense, frameshift or splice site mutations in REN result in undetectable expression of renin RNA or protein in kidney sections (PMID: 16116425; PMID: 22095942). Conversely, biallelic non-truncating mutations or missense mutations of the active site altered renin trafficking and sorting resulting in marked kidney accumulation of defective renin with a dramatically low level of plasma active renin (PMID: 22095942). Aberrant function of renin (as well as other RAS components) affects nephron development and causes the RTD phenotype.

This gene-disease association is supported by immunohistochemical studies of renin in kidney biopsies of affected individuals, determination of active renin in plasma, experimental cellular models and a knockout rat model (PMID: 21036942; PMID: 21242461). In summary, there is DEFINITIVE evidence to support the relationship between REN and autosomal recessive renal tubular dysgenesis (RTD). 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 10/28/2020 (SOP Version 7).