PSMD12 was first reported in relation to autosomal dominant Stankiewicz-Isidor Syndrome (STISS) in 2017 (Kury et al. 2017, PMID: 28132691). STISS is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral issues, mild craniofacial anomalies and variable congenital defects. Ten variants (8 nonsense and 2 splice site) that have been reported in 10 probands in 3 publications (PMIDs: 28132691, 30421579, 34906456) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by an animal model (PMIDs: 28132691). A PSMD12 zebrafish CRISPR/Cas9 knockout model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology consistent with phenotypes in individuals with STISS (PMIDs: 28132691).
In summary, there is definitive evidence supporting the relationship between PSMD12 and autosomal dominant Stankiewicz-Isidor Syndrome. 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 Intellectual Disability and Autism GCEP on March 5, 2024 (SOP Version 10).
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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