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SETBP1 gene: An important gene associated with isolated speech or language disorder and mild mental retardation.

Maricia Cutrupi, Maria Rosa Pizzino, Laura Colavita, Silvana Briuglia, Carmelo Salpietro
Department of Adult and Childhood Pathology, Unit of Genetics and Pediatric Immunology, University Hospital of Messina, Messina, Italy

Case Report
A 7 years old boy was referred for genetic counseling because presented psychomotor developmental delay and impairment of expressive language. The patient was the first child of a non consanguineous Chinese parents. The family history did not document congenital anomalies or mental retardation. The boy was born at 40 week of gestation after fisiological pregnancy. Birth weight was 3, 250 g (10-25th centile), length 50 cm. No other disease in clinical history.
Microarray-based comparative genomic hybridisation (aCGH) analyses were performed to identify genetic causes for developmental and expressive speech delay in our patient.
Array-CGH analysis showed an interstitial proximal microdeletion of chromosome 18 of 2, 65 Mb arr18q12.3 (39.823.856-42469.362) x1 dn. The critical deleted region contains SETBP1 gene (SET binding protein 1) (Fig 1) .
Children with an isolated speech or language disorder and mild mental retardation are not often genetically evaluated, despite recent evidence supporting a role for genetic factors in the aetiology of these disorders. Several chromosomal copy number variants and single gene disorders associated with abnormalities of speech and language have been identified (Fig 2) .
Currently, Array Comparative Genomic Hybridization (array CGH) is also recommended by the International Standards for Cytogenomic Arrays (ISCA) Consortium as a first line test in the diagnostics of Intellectual disability (ID) /Developmental delay (DD), replacing G-banded chromosome analysis. Ther are various chromosomal aberrations that are associated with speech and language pathology and can occur in the setting of normal or only mildly impaired cognitive function. In particular, the interstitial proximal microdeletion of chromosome 18 affecting multiple genes including SETBP1 (OMIM 611060) . This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The gene is expressed in numerous tissues and multiple transcript variants encoding different isoforms have been found. In particular, the deletion here described affects transcript variant 1, the longer transcript that encodes the longer isoform, which expression was found in the brain (Minakuchi M. et al., 2001) .
SETBP1 is oncogene and specific somatic mutations of this gene were discovered in patients affected by atypical Chronic Myeloid Leukemia (aCML) and related diseases.
Missense heterozygous mutations cause Schinzel-Giedion syndrome (SGS, MIM#269150) . The syndrome is characterized by profound and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia. The distinctive facial dysmorphism are prominent forehead, midface retraction resembling a broadened ''figure-of-eight'' in marked cases, and a short upturned nose. Prognosis is severe, with most affected patients not surviving infancy due to the progressive neurodegeneration, increased risk of tumors, recurrent infections and respiratory failure. The severe phenotype associated with SETBP1 point mutations was proposed to be consequence of a gain-of-function or dominant-negative effect of the mutations. (Hoischen A et al 2010; Suphapeetiporn K et al., 2011) Most affected individuals die before the age of ten. (Hoischen A et al., 2010) .
Several cases of interstitial deletion encompassing band 18q12.3 are described in patients with mild dysmorphic features, mental retardation and impairment of expressive language. Haploinsufficiency of SETBP1 has been postulated as the causative gene for expressive speech delay in individuals with this chromosome deletions. Recently, a 18q12.3 microdeletion causing SETBP1 haploinsufficiency has been described in two patients that show expressive speech impairment, moderate developmental delay and peculiar facial features. (Filger et al., 2011) . Marseglia et al., (2012) described an additional patient with the smallest 18q12.3 microdeletion never reported that causes the disruption of SETBP1. The patient shows mild mental retardation and expressive speech impairment with striking discrepancy between expressive and receptive language skills. A complete lack of expressive speech with intact receptive language abilities has been noted in several individuals. The variable dysmorphic features are brachycephaly, dolicocephaly, long face, downslanting palpebral fissures hypertelorism ptosis synophrys full nasal tip pointed chin, thin upper lip. Other features are behavioral difficulties, seizures or EEG abnormalities, decreased fine motor skills, and autistic traits. SETBP1 expression was reduced in a patient with SETBP1 haploinsufficiency, indicating that the SETBP1 deletion phenotype is allele dose sensitive.
During the past few years, advances in genetic technology have led to the identification of several chromosomal CNVs and single gene changes associated with abnormalities of speech and language. In contrast to genetic syndromes, disorders of speech/language may be overlooked as they often present without clearly defined clinical features. This is particularly true when speech or language problems are the main presenting symptom in a child who has only mild developmental delay or otherwise normal development. In this contest, array CGH has become an important tool for clinical diagnostics and gene identification studies and is having a graeat impact on the understending of pathologies the counseling of families and patient management.

Fig1:Chr 18

Filges I, Shimojima K, Okamoto N, Röthlisberger 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. 2011Feb;48 (2) :117-22.
A. Hoischen, B.W. van Bon, C. Gilissen, P. Arts, B. van Lier, M. Steehouwer, P. de Vries, R. de Reuver, N. Wieskamp, G. Mortier, K. Devriendt, M.Z. Amorim, N. Revencu, A. Kidd, M. Barbosa, A. Turner, J. Smith, C. Oley, A. Henderson, I.M. Hayes, E.M. Thompson, H.G. Brunner, B.B. de Vries, J.A. Veltman, De novo mutations of SETBP1 cause Schinzel-Giedion syndrome, Nat. Genet. 42 (6) (2010) 483e485.
Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R,
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. ETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010 Jun;42 (6) :483-5.
M. Minakuchi, N. Kakazu, M.J. Gorrin-Rivas, T. Abe, T.D. Copeland, K. Ueda, Y. Adachi, Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET, Eur. J. Biochem. 268 (2001) 1340e1351.
K. Suphapeetiporn, C. Srichomthong, V. Shotelersuk, SETBP1 mutations in two Thai patients with Schinzel-Giedion syndrome, Clin. Genet. 79 (4) (2011) 391e393.

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www.thechild.it Four-monthly Journal of Pediatrics edited by Genetics and Pediatric Association (APIG)
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