KCNJ1 was first reported in relation to autosomal recessive Bartter disease type 2 in 1996 (Simon et al., PMID: 8841184). Bartter syndrome is characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Antenatal Bartter syndrome (type 2) presents with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. 13 variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 8 probands in 2 publications (PMIDs: 8841184, 19096086) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (animal models, expression studies, biochemical function, and in vitro functional assays) (PMIDs: 7635463, 9580661, 12086641, 12122007, 24400161). It was demonstrated that decreased potassium channel-PIP2 interactions underlies the molecular mechanism of Bartter syndrome when KCNJ1 variants are present in patients. Furthermore, KCNJ1 is normally expressed in the kidney with variation causing disturbed currents across the potassium channel as functionally demonstrated in multiple variants, c.584C>T (p.Ala195Val), c.600C>G (p.Ser200Arg), c.939_942del (p.Glu315fs), and c.601C>T (p.Leu201Phe). Finally, the KCNJ1 knockout mouse model generated by Lorenz et al., PMID: 12122007, was well cited and recapitulated the reduction of renal salt reabsorption as seen in patients with Bartter disease type 2. In summary, KCNJ1 is definitively associated with autosomal recessive Bartter disease type. 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 Tubulopathy GCEP on the meeting date June 16, 2022 (SOP Version 9).
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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