DCDC2 was first reported in relation to autosomal recessive renal-hepatic ciliopathy as early as 2015 (Schueler et al. 2015; PMID: 25557784). DCDC2 is associated with Nephronophthisis 19 (OMIM:616217) and Neonatal Sclerosing Cholangitis (OMIM:617394) in OMIM, each with variable renal and hepatic involvement, but both with phenotypes related to abnormal cilia function. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found little difference in molecular mechanism, inheritance pattern and phenotypic variability between the two disease entities and therefore, they have been lumped into one disease entity, ciliopathy (MONDO:0005308). At least 5 variants (nonsense, frameshift, and splice site) have been reported in 7 patients in 3 publications (PMIDs: 25557784, 27469900, 31821705). The mechanism of pathogenicity appears to be loss of function variants that inhibit the Wnt signalling pathway and affect primary cilia signalling, leading to impaired tubulin binding and microtubule polymerization. This gene-disease association is also supported by an animal model and expression study (PMID: 25557784). In summary, DCDC2 is definitively associated with autosomal recessive ciliopathy-DCDC2. 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 Cystic and Ciliopathy Disorders GCEP on 10/13/21 (SOP Version 8).
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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