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Case Reports
. 2009;125(1):1-7.
doi: 10.1159/000218743. Epub 2009 Jul 14.

Constitutional haploinsufficiency of tumor suppressor genes in mentally retarded patients with microdeletions in 17p13.1

A C V Krepischi-Santos  1 , D Rajan, I K Temple, V Shrubb, J A Crolla, S Huang, S Beal, P A Otto, N P Carter, A M Vianna-Morgante, C Rosenberg
Affiliations
Case Reports

Constitutional haploinsufficiency of tumor suppressor genes in mentally retarded patients with microdeletions in 17p13.1

A C V Krepischi-Santos et al. Cytogenet Genome Res. 2009.

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.

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Figures

Fig. 1.
Fig. 1.
Facial features of patients carrying deletions in 17p13.1. a Patient 1, 3 years of age. b Patient 2, 8 years of age. c Patient 3, 6 years of age. d Patient 4, 18 years of age.
Fig. 2.
Fig. 2.
Array-CGH profile of the most distal 10 Mb of 17p13 in the Brazilian patients. The red box on the idiogram shows the segment containing the deletions. For patient 4, who has the deletion in ∼50% of the cells, the log2 ratio value is intermediate between normal copy number and non-mosaic deletions.
Fig. 3.
Fig. 3.
Chromosomal alterations detected in patient 4. a Mosaic deletion at 17p13.1, as revealed by FISH (∼50% of metaphases of cultured lymphocytes): metaphase with the fluorescent signal of BAC RP11-144K9 on both chromosomes 17 and a nucleus with a single signal (arrows). b Deletion at 3q29 present in the patient and his mother. Left side: array-CGH profile in the patient; right side: FISH on a metaphase from the patient's mother, showing the red fluorescent signal of BAC GS-56-H22 on only one chromosome 3 (arrows).
Fig. 4.
Fig. 4.
Mapping of deletions in 17p13. a Schematic representation of the deletions in the 4 patients depicting the minimum overlapping region in 17p13.1. The green bar represents a gene relevant for the phenotype of patient 4. b Enlargement of this region, showing the 18 genes therein (Ensembl Genome Browser; August 2008). The blue bars represent genes that have a role in neuronal development/function, while orange bars indicate genes with known or suspected tumor suppression activity.
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