Submission Details

SETBP1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder as early as 2011 (Filges et al., PMID: 21037274). Clinical features observed in individuals with variants in SETBP1 include intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, behavior challenges, and facial dysmorphisms. At least 20 unique loss-of-function (LOF) variants (nonsense, frameshift, large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data. This curation includes 7 probands described in 4 publications to reach the maximum score for genetic evidence (12 points; PMIDs: 23020937, 25217958, 29463886, 25356899); however, more evidence is available in the literature. The mechanism of disease is proposed to be haploinsufficiency (PMID: 21037274). Of note, germline missense variants in SETBP1, particularly variants affecting amino acids 868-871, have been implicated in Schinzel-Giedion syndrome, which will be assessed separately. Clinical features of Schinzel-Giedion syndrome include severe intellectual disability, facial dysmorphisms, and congenital anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF) causing SETBP1 protein to accumulate (PMID: 28346496). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms between LOF variants associated with complex neurodevelopmental disorder and GOF missense variants associated with Schinzel-Giedion syndrome. In summary, SETBP1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This curation was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 10/20/2020.