SETBP1 was first reported in relation to autosomal dominant Schinzel-Giedion syndrome (SGS) as early as 2010 (Hoischen et al., PMID: 20436468). Clinical features of this disorder include developmental delay, seizures, facial dysmorphisms, and genitourinary and skeletal anomalies. At least 13 unique missense variants have been reported in humans, and more than 50 individuals with a genetic diagnosis of SGS have been described in the literature (PMID: 28346496). Evidence supporting this gene-disease relationship includes case-level data and variant-level functional assays. This curation includes 15 probands described in 10 publications to reach the maximum score for genetic evidence (12 points; PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496); however, more evidence is available in the literature. The mechanism of disease is proposed to be gain of function resulting in an increase in SETBP1 protein (PMID: 28346496).
Of note, loss of function variants in SETBP1 have been definitively associated with autosomal dominant complex neurodevelopmental disorder, which is characterized by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, behavior challenges, and less severe facial dysmorphisms (described as “autosomal dominant mental retardation 29” in OMIM [MIM: 616078]). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these disorders have been curated separately due to differences in molecular mechanism and phenotypic variability.
In summary, there is definitive evidence to support the relationship between SETBP1 and autosomal dominant Schinzel-Giedion syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 2/16/21 (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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