Submission Details

NEK8 was first reported in relation to autosomal recessive nephronophthisis (NPHP9; OMIM: 613824) by Otto et al in 2008 (PMID:8199800) and to autosomal recessive renal-hepatic-pancreatic dysplasia (RHPD2; OMIM: 615415), where there are cysts in the kidney, liver and pancreas, and often cardiac anomalies and bowed femora, by Rajagopalan et al in 2016 (PMID:26697755). Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found no difference in the molecular mechanisms or inheritance pattern. Therefore both of these disease entities were lumped into one disease entity. Null variants, splicing variants and missense variants in NEK8 have been reported in at least 6 probands in 4 publications (PMIDs: 18199800, 26697755, 26862157, 26967905). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is biallelic loss of function. This gene-disease association is also supported by protein interactions, expression studies, functional alterations in patient and non-patient cells, non-human model organisms, cell culture models, and rescue of both a model organisms and cell culture models (PMIDs: 12421721, 18235101, 23274954, 23793029, 26967905). In summary, NEK8 is definitively associated with autosomal recessive renal-hepatic-pancreatic dysplasia 2. This has been reportedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. There was however some discussion about whether this condition should be called a ciliopathy rather than a form of nephronophthisis since the clinical features were more consistent with a ciliopathy. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP Working Group on 9/8/2021 (SOP Version 8).