SETBP1 – Autosomal Dominant Intellectual Disability 29

SETBP1 encodes the SET binding protein 1, a transcriptional regulator implicated in neurodevelopment. Heterozygous loss-of-function variants in SETBP1 cause Intellectual Disability, Autosomal Dominant 29 (MONDO:0014482), characterized by moderate intellectual disability, expressive language delay, and speech apraxia.

Clinical genetic evidence supports autosomal dominant inheritance. Three unrelated case reports describe de novo SETBP1 disruptions: a balanced translocation disrupting exons 2–3 (t(12;18)(q22;q12.3)) in a patient with moderate intellectual disability and speech impairment (PMID:35769969), a heterozygous c.1724_1727del (p.Asp575ValfsTer4) frameshift in a mother–fetus pair with SETBP1-HD features (PMID:37150818), and a de novo nonsense variant c.532C>T (p.Gln178Ter) in a child with speech apraxia and delayed bone age (PMID:38585550).

A systematic cohort study of 34 individuals with SETBP1 haploinsufficiency disorders identified heterozygous loss-of-function variants—including nonsense, frameshift, splice, and single exon deletions—in all cases confirmed by molecular diagnostics (PMID:33867525). The most common clinical features were mild motor delay, speech impairment, moderate intellectual disability, hypotonia, attention deficits, and hyperactivity, without a distinct facial gestalt.

The variant spectrum in SETBP1-HD comprises primarily frameshift and nonsense changes across the 18q12.3 locus, consistent with haploinsufficiency. No recurrent or founder variants have been reported; all variants are private and de novo. Total probands: 37; loss-of-function variants: 37 (34 cohort + 3 case reports).

Functional studies demonstrate that SETBP1 haploinsufficiency reduces gene expression in patient fibroblasts (PMID:21037274). Induced pluripotent stem cell–derived neural models with truncating SETBP1 variants exhibit altered WNT and RNA polymerase II pathways concordant with neurodevelopmental deficits, supporting haploinsufficiency as the mechanism.

No studies have disputed the role of SETBP1 loss-of-function in MRD29, and gain-of-function variants causing Schinzel–Giedion syndrome present with distinct severe multisystem features. Thus, the gene–disease relationship is robust and specific to haploinsufficiency for Intellectual Disability, Autosomal Dominant 29.

Integration of genetic and experimental data establishes SETBP1 haploinsufficiency as a strong cause of autosomal dominant intellectual disability, guiding molecular diagnosis, genetic counseling, and patient management. Key Take-home: Heterozygous loss-of-function SETBP1 variants are diagnostic for Intellectual Disability, Autosomal Dominant 29, enabling targeted clinical care.

References

• European Journal of Human Genetics • 2021 • Clinical delineation of SETBP1 haploinsufficiency disorder. PMID:33867525
• Journal of Pediatric Genetics • 2022 • A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder. PMID:35769969
• Orphanet Journal of Rare Diseases • 2023 • Identification of a novel de novo mutation of SETBP1 and new findings of SETBP1 in tumorgenesis. PMID:37150818
• Molecular Syndromology • 2024 • Delayed Bone Age in a Child with a Novel Loss-of-Function Variant in SETBP1 Gene Sheds Light on the Potential Role of SETBP1 Protein in Skeletal Development. PMID:38585550
• Journal of Medical Genetics • 2011 • Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome. PMID:21037274

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