title: Constitutional haploinsufficiency of tumor suppressor genes in mentally retarded patients with microdeletions in 17p13.1.
abstract: Chromosome microdeletions or duplications are detected in 10-20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of approximately 180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (approximately 1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer.
authors.affiliation: Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: A C V
authors.initials: AC
authors.lastname: Krepischi-Santos
authors.forename: D
authors.initials: D
authors.lastname: Rajan
authors.forename: I K
authors.initials: IK
authors.lastname: Temple
authors.forename: V
authors.initials: V
authors.lastname: Shrubb
authors.forename: J A
authors.initials: JA
authors.lastname: Crolla
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: S
authors.initials: S
authors.lastname: Beal
authors.forename: P A
authors.initials: PA
authors.lastname: Otto
authors.forename: N P
authors.initials: NP
authors.lastname: Carter
authors.forename: A M
authors.initials: AM
authors.lastname: Vianna-Morgante
authors.forename: C
authors.initials: C
authors.lastname: Rosenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D014166:Transferases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C116741:GABARAP protein, human; C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D015221:Potassium Channels; C488725:KCTD11 protein, human; D014166:Transferases