NEK8 (Never in Mitosis Gene A-related kinase 8) was first associated with monoallelic (AD) cystic kidney disease by Claus in 2023 (PMID: 37598857). NEK8 is a serine-threonine protein kinase that is critical in cell cycle regulation through Hippo signaling. NEK8 also appears to regulate polycystin 2 targeting to the cilia. It is required for kidney tubular cell cytoskeletal structure; renal and cardiovascular development; and for left-right symmetry. In this initial report, cysts were found first in infancy with no extrarenal manifestations in contrast to biallelic NEK8 disease (AR). Biallelic disease is associated with nephronophthisis 9 and renal-hepatic-pancreatic dysplasia 2, where there are cysts in the kidney, liver and pancreas and often extra-renal features.
Only a few variants have been reported in monoallelic NEK8 and these are all missense changes that affect the kinase domain. In this initial report, one variant p.Arg45Trp was reported in 10 families, 6 with proven de novo mutations. One other report associated de novo NEK8 p.Arg45Trp with infantile cystic kidneys [PMID: 36215968]. The mechanism is toxic gain of function. This gene-disease relationship is also supported by biochemical function, protein interactions and expression, as well as functional alteration in patient cells, and evidence from a cell culture model and rescue in the cell culture model.
In summary, there is Strong evidence to support the relationship between NEK8 and AD polycystic kidney disease. This has been demonstrated in both the research and the clinical diagnostic settings. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 01/08/2024 (SOP Version 10).
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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