SETBP1

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: ClinGen

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. In individuals with classic SGS, which is caused by pathogenic variants in a mutational hotspot of SETBP1, there is also an increased prevalence of embryonal tumours, particularly neuroepithelial neoplasms, including teratomas, primitive neuroectodermal tumours, and ependymomas (PMIDs: 7506484, 12847324, 28451008, 8849020, 28346496, 7864048, 9738870, 20436468, 17165030, 28346496, 28346496). 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 originally approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 2/16/21 (SOP Version 8). The Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP reviewed this curation on 4/14/2026. As a result of this reevaluation, the classification did not change. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on 4/14/2026.

Inheritance Pattern: AD

Disease ID:MONDO:0014482

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0014482

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0010010

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018574

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014482

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*SETBP1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (Filges et al., PMID: 21037274). Clinical features observed in individuals with variants in *SETBP1* include developmental delay, intellectual disability, autism, speech difficulty, seizures, hypotonia, behavior challenges, and facial dysmorphisms. At least 20 unique loss-of-function (LoF) variants (nonsense, frameshift, and large deletions) have been reported. This curation includes 7 probands reported in 4 publications (PMIDs: 23020937, 25217958, 25356899, 29463886). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. 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 the SETBP1 protein to accumulate (PMID: 28346496). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, 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, there is definitive evidence supporting the relationship between *SETBP1* and autosomal dominant complex neurodevelopmental disorder. 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 October 20, 2020 (SOP version 7).