WDR19 was first reported in relation to autosomal recessive ciliopathies in 2011 (Bedrup et al., PMID: 22019272). Evidence supporting this gene-disease relationship includes case-level data and experimental data. WDR19 has been noted to be associated with the following disease entities: Cranioectodermal dysplasia 4 (OMIM:614378), Nephronophthisis 13 (OMIM:614377), Senior-Loken syndrome 8 (OMIM:616307), and Short-rib thoracic dysplasia 5 with or without polydactyly (OMIM:614376). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and the phenotypic variability was representative of a syndromic spectrum of ciliopathy disorders caused by WDR19. Therefore, the above disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). The mechanism of pathogenicity is reported to be loss of function. Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 22019272, 23683095, 23559409, 25726036) and are included in this curation. Additionally, variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies, functional alteration studies, and animal models. (PMIDs: 33517396, 22228095, 25726036, 22019273). Expression studies demonstrated a reduction in ciliated cells, a lack of WDR19 in cilia, and diffuse cytoplasmic staining in cells from affected patients. Exogenous expression of WDR19 variants in WDR19-knockout cells did not rescue ciliogenesis defects. Finally, ENU-derived mice with a hypomorphic missense mutation (p.Leu750Pro) in Wdr19 replicate skeletal and craniofacial anomalies seen in human skeletal ciliopathies. In summary, WDR19 is definitively associated with autosomal recessive ciliopathy. 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 Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 5/25/22 (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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