SETBP1 haploinsufficiency disorder is a condition that involves speech and language problems, intellectual disability, and distinctive facial features.

In people with SETBP1 haploinsufficiency disorder, problems with vocabulary and the production of speech (expressive language skills) are generally more severely affected than the ability to understand speech (receptive language skills). About 80 percent of affected children have a condition called childhood apraxia of speech, in which they have difficulty with the mouth movements needed to speak. Speech development may be limited to a few words or no speech. Affected individuals often communicate using gestures or by mimicking the expressions of others.

Individuals with SETBP1 haploinsufficiency disorder have intellectual disability that can range from mild to moderate. They may also have neurodevelopment problems, such as attention-deficit/hyperactivity disorder (ADHD) or autistic behaviors that affect communication and social interaction. Affected individuals may have weak muscle tone (hypotonia); delayed development of motor skills, such as sitting, standing, and walking; or recurrent seizures (epilepsy).

Distinctive facial features in people with SETBP1 haploinsufficiency disorder can include a long face, a high forehead, eyebrows that grow together in the middle (synophrys), short eye openings (short palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), droopy eyelids (ptosis), puffiness of the skin around the eyes (periorbital fullness), small nostrils, a high nasal bridge, a broad tip of the nose, a thin upper lip, a high arch in the roof of the mouth (high-arched palate), and a small chin.

The exact prevalence of SETBP1 haploinsufficiency disorder is unknown, although it is thought to be a rare disorder. At least 45 affected individuals have been described in the scientific literature.

SETBP1 haploinsufficiency disorder is caused by variants (also called mutations) in the SETBP1 gene. This gene provides instructions for making a protein that attaches (binds) to certain regions of DNA to increase gene activity (expression). The SETBP1 protein is found throughout the body, but protein levels are highest during brain development before birth. During this time, nerve cells grow and divide (proliferate) and move (migrate) to their proper location in the brain. The SETBP1 protein is thought to control the activity of genes involved in these developmental processes.

SETBP1 gene variants that cause SETBP1 haploinsufficiency disorder prevent the production of any functional SETBP1 protein from one copy of the gene. It is unclear how the loss of SETBP1 protein leads to the specific features of SETBP1 haploinsufficiency disorder. A shortage of this protein probably impairs the expression of certain genes in the brain, disrupting development. Abnormalities in certain brain regions likely underlie the speech, intellectual, and behavioral problems that can occur in SETBP1 haploinsufficiency disorder.

Genetic Testing Information

• Genetic Testing Registry: Intellectual disability, autosomal dominant 29

Genetic and Rare Diseases Information Center

• Intellectual developmental disorder, autosomal dominant 29

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 29; MRD29

Scientific Articles on PubMed

• PubMed

• Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LE, Schuurs-Hoeijmakers JH, Hoischen A, Pfundt R, Krumm N, Carvill GL, Li D, Amaral D, Brown N, Lockhart PJ, Scheffer IE, Alberti A, Shaw M, Pettinato R, Tervo R, de Leeuw N, Reijnders MR, Torchia BS, Peeters H, O'Roak BJ, Fichera M, Hehir-Kwa JY, Shendure J, Mefford HC, Haan E, Gecz J, de Vries BB, Romano C, Eichler EE. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014 Oct;46(10):1063-71. doi: 10.1038/ng.3092. Epub 2014 Sep 14. Citation on PubMed or Free article on PubMed Central
• Filges I, Shimojima K, Okamoto N, Rothlisberger B, Weber P, Huber AR, Nishizawa T, Datta AN, Miny P, Yamamoto T. Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome. J Med Genet. 2011 Feb;48(2):117-22. doi: 10.1136/jmg.2010.084582. Epub 2010 Oct 30. Citation on PubMed
• Jansen NA, Braden RO, Srivastava S, Otness EF, Lesca G, Rossi M, Nizon M, Bernier RA, Quelin C, van Haeringen A, Kleefstra T, Wong MMK, Whalen S, Fisher SE, Morgan AT, van Bon BW. Clinical delineation of SETBP1 haploinsufficiency disorder. Eur J Hum Genet. 2021 Aug;29(8):1198-1205. doi: 10.1038/s41431-021-00888-9. Epub 2021 Apr 19. Citation on PubMed
• Marseglia G, Scordo MR, Pescucci C, Nannetti G, Biagini E, Scandurra V, Gerundino F, Magi A, Benelli M, Torricelli F. 372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment. Eur J Med Genet. 2012 Mar;55(3):216-21. doi: 10.1016/j.ejmg.2012.01.005. Epub 2012 Jan 25. Citation on PubMed
• Morgan A, Braden R, Wong MMK, Colin E, Amor D, Liegeois F, Srivastava S, Vogel A, Bizaoui V, Ranguin K, Fisher SE, van Bon BW. Speech and language deficits are central to SETBP1 haploinsufficiency disorder. Eur J Hum Genet. 2021 Aug;29(8):1216-1225. doi: 10.1038/s41431-021-00894-x. Epub 2021 Apr 27. Citation on PubMed
• Morgan A, Srivastava S, Duis J, van Bon B. SETBP1 Haploinsufficiency Disorder. 2021 Nov 18 [updated 2024 May 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK575336/ Citation on PubMed
• Perdue MV, Mascheretti S, Kornilov SA, Jasinska KK, Ryherd K, Einar Mencl W, Frost SJ, Grigorenko EL, Pugh KR, Landi N. Common variation within the SETBP1 gene is associated with reading-related skills and patterns of functional neural activation. Neuropsychologia. 2019 Jul;130:44-51. doi: 10.1016/j.neuropsychologia.2018.07.015. Epub 2018 Aug 23. Citation on PubMed or Free article on PubMed Central