Variants in ZBTB20 zinc finger regions were first reported in individuals with autosomal dominant Primrose syndrome in 2014 (Cordeddu et al., PMID: 25017102). Phenotypes commonly reported with ZBTB20 variants include macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, facial dysmorphic features, calcification of the external ear cartilage, sparse body hair, skeletal anomalies, distal muscle wasting, contractures, decreased bone mineral density, hearing loss, ocular anomalies, cryptorchidism, findings on brain imaging and altered glucose metabolism (PMID: 33956417). Both missense and putative loss of function variants in ZBTB20 have been reported in individuals with overlapping features; additionally, ZBTB20 is the main candidate gene for the 3q13.31 microdeletion syndrome, which also shares clinical features with Primrose syndrome. Individuals with deletions and putative loss of function variants appear to have milder manifestations, while individuals with missense variants appear to be more severely affected. Evidence suggests that the more severe missense variants are acting via a dominant negative effect. Because the phenotypes of individuals with loss of function and dominant negative variants overlap and appear to be part of the same clinical spectrum, the ClinGen ID/Autism GCEP is curating all of this information together under the disease term Primrose syndrome.
Seventeen variants (missense, in-frame deletion, frameshift), reported in seventeen probands in five publications (PMIDs: 25017102, 32266967, 30637921, 29737001, 32266967) are included in this curation. The variant p.Met625Val is recurrent and has been reported two times in the published literature (PMIDs: 31321892, 32266967). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence.
In summary, there is definitive evidence to support the relationship between ZBTB20 and Primrose syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 18th, 2023 (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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