POLR1D has been repeatedly described in association with autosomal dominant Treacher Collins Syndrome 2 (TCS2). TCS2 is a disorder of craniofacial development characterized by downward slanting palpebral fissures, coloboma, hypoplasia of the facial bones, cleft palate, malformation of the external ears, and bilateral conductive hearing loss. At least 3 missense and 5 nonsense variants have been reported in at least 10 probands from 5 publications (PMIDs: 21131976, 25790162, 31107123, 34397304, 34136434). In addition to these variants, there has been one missense variant (p.Leu55Val) determined to have an autosomal recessive mode of inheritance in three unrelated probands (PMIDs: 24603435, 25790162). However, this information was not scored for autosomal dominant TCS2. This gene disease association is also supported by experimental evidence including protein interactions and an animal model (PMIDs: 8955128, 27448281). In summary, POLR1D is definitively associated with autosomal dominant Treacher Collins Syndrome 2. 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 Craniofacial Malformations Gene Curation Expert Panel on 12/15/2022. (SOP Version 9)
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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