KCNJ16 was first reported in relation to autosomal recessive hypokalemic tubulopathy and deafness, in 2021 (Schlingmann et al., 2021; PMID: 33811157).
9 variants (missense and nonsense) that have been reported in at least 10 probands in 3 publications (PMIDs: 33811157, 33840812, 37466410) are included in this curation. There were two additional cases of genetic evidence referenced in the curation, but these were not scored due to high allele frequency/evidence for benign impact of the variants (PMIDs: 39414394, 39467953). The mechanism of pathogenicity appears to be loss-of-function. This gene-disease association is also supported by experimental evidence (ie. rat/mouse models, expression-level evidence, biochemical functional evidence, interaction evidence; PMIDs: 21633011, 21047793, 28931751). Expression-level data from GTEx and Humphrey's lab shows expression in the kidney, especially the distal convoluted tubule. Rat/mouse model evidence indicates that mutants have hypotension; excessive urination with hypokalemic metabolic acidosis; and abnormally high levels of potassium, calcium, and magnesium in urine. Biochemical functional evidence shows that the protein forms a heterodimer channel with KCNJ10 to allow potassium into the cell, which helps maintain electrolyte homeostasis. KCNJ10 is definitive for autosomal EAST Syndrome (Epilepsy, Ataxia, Sensorineural Deafness, and Renal Tubulopathy). This is relevant since EAST Syndrome includes salt-wasting renal tubulopathy. There was also an kidney organoid model found (PMID: 39183338), but this was not scored since it is not as informative as a in vivo model.
This gene-disease pair was originally evaluated by the Tubulopathy GCEP on December 7, 2022. It was reevaluated on October 1, 2025 (SOP Version 11). As a result of this reevaluation, the classification increased from strong to definitive with the addition of genetic evidence (PMID: 37466410) that fulfilled the replication over time requirement.
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.