ZNF423 was first reported in relation to autosomal recessive ciliopathy in 2012 (Chaki et al., PMID: 22863007). ZNF423 has been noted to be associated with the following disease entities: Nephronophthisis 14 (NPHP14) and Joubert Syndrome 19 (JBTS19). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and phenotypic variability. Inheritance patterns show that NPHP14 is caused by biallelic variants while JBTS19 is caused by heterozygous variants in ZNF423. Since the significance of the JBTS patients with a single variant is not clear, this data was not scored (PMIDs: 22863007, 31216405). Therefore, the two disease entities have been lumped into one disease entity: ciliopathy (OMIM:614844). At least 11 unique variants (missense) have been reported in 7 individuals in 7 publications (PMIDs: 22863007, 26539891, 28454995, 33531950, 30076350, 31964843, 30868567). The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by biochemical function, functional alteration, protein interaction studies, and mouse models (PMID: 17151198, 17524391, 22863007, 27727273, 33517396). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on March 23, 2022. It was re-evaluated on June 26, 2024 as per SOP version 10. As a result of this reevaluation, the classification increased from Limited to Moderate with the addition of a new case-level and experimental evidence (PMIDs: 26539891, 28454995, 27727273, 30868567).
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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