Early onset or syndromic epilepsy

Gene: SETBP1

Green List (high evidence)

SETBP1 is associated with two distinct autosomal dominant disorders: Intellectual developmental disorder, known as SETBP1 disorder, and Schinzel-Giedion syndrome.

SETBP1 disorder is characterised by intellectual disability, autism, speech difficulty, motor and developmental delays, seizures, hypotonia, and facial dysmorphisms (PMID: 21037274). The mechanism of disease is haploinsufficiency (PMID: 21037274).
There are at least 7 unrelated individuals reported in literature, diagnosed with SETBP1 disorder and harbouring LOF variants in SETBP1 (nonsense, frameshift, large deletions) - PMIDs: 23020937, 25217958, 29463886, 25356899.

Schinzel-Giedion syndrome is caused by missense variants in SETBP1, particularly variants affecting amino acids 868-871 - a specific ‘hotspot’ region of the SETBP1 gene that codes for a degron. Clinical features of Schinzel-Giedion syndrome include developmental delay, epilepsy, facial dysmorphisms, and genitourinary and skeletal anomalies. The proposed mechanism of Schinzel-Giedion syndrome is gain-of-function (GOF), causing SETBP1 protein to accumulate (PMID: 28346496). There are at least 15 unrelated individuals with Schinzel-Giedion syndrome and heterozygous missense variants in SETBP1 reported in literature (PMIDs: 20436468, 26188272, 32460883, 22473152, 25028416, 25082129, 25663181, 26096993, 32445275, 28346496).

SETBP1 is associated with Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078 and Schinzel-Giedion midface retraction syndrome, OMIM: 269150 (OMIM, accessed 28th Oct 2025).

Created: 28 Oct 2025, 12:24 p.m. | Last Modified: 28 Oct 2025, 12:24 p.m.

Panel Version: 8.59

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder, autosomal dominant 29, OMIM: 616078; Schinzel-Giedion midface retraction syndrome, OMIM: 269150; Schinzel-Giedion syndrome, MONDO:0010010

Publications

• 20436468
• 21037274
• 22473152
• 23020937
• 25217958
• 25356899
• 25028416
• 25082129
• 25663181
• 26096993
• 26188272
• 28346496
• 29463886
• 32445275
• 32460883

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

Gain of function mutations (exon 4) [PMID: 28346496], loss of function mutations have been reported to cause ID with seizures [PMID: 25217958].

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation autosomal dominant 29,616078; Schinzel-Giedion midface retraction syndrome, 269150

Publications

• 25217958
• 28346496

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in twelve unrelated cases in which seizures are a phenotypic feature.

Created: 3 Dec 2018, 4:01 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this syndrome.

Created: 21 Aug 2018, 9:20 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Schinzel-Giedion midface retraction syndrome, MIM#269150

Variants in this GENE are reported as part of current diagnostic practice