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San Giovanni Rotondo, Italy

Bernardini L.,San Giovanni Rotondo and CSS Mendel Institute | Alesi V.,San Giovanni Rotondo and CSS Mendel Institute | Alesi V.,Thomas Jefferson University | Loddo S.,San Giovanni Rotondo and CSS Mendel Institute | And 11 more authors.
European Journal of Human Genetics | Year: 2010

We used Affymetrix 6.0 GeneChip SNP arrays to characterize copy number variations (CNVs) in a cohort of 70 patients previously characterized on lower-density oligonucleotide arrays affected by idiopathic mental retardation and dysmorphic features. The SNP array platform includes 900 000 SNP probes and 900 000 non-SNP oligonucleotide probes at an average distance of 0.7 Kb, which facilitates coverage of the whole genome, including coding and noncoding regions. The high density of probes is critical for detecting small CNVs, but it can lead to data interpretation problems. To reduce the number of false positives, parameters were set to consider only imbalances 75 Kb encompassing at least 80 probe sets. The higher resolution of the SNP array platform confirmed the increased ability to detect small CNVs, although more than 80% of these CNVs overlapped to copy number neutral polymorphism regions and 4.4% of them did not contain known genes. In our cohort of 70 patients, of the 51 previously evaluated as normal on the Agilent 44K array, the SNP array platform disclosed six additional CNV changes, including three in three patients, which may be pathogenic. This suggests that about 6% of individuals classified as normal using the lower-density oligonucleotide array could be found to be affected by a genomic disorder when evaluated with the higher-density microarray platforms. © 2010 Macmillan Publishers Limited All rights reserved. Source


Chiaretti S.,University of Rome La Sapienza | Tavolaro S.,University of Rome La Sapienza | Marinelli M.,University of Rome La Sapienza | Messina M.,University of Rome La Sapienza | And 14 more authors.
Genes Chromosomes and Cancer | Year: 2011

Given that TP53 alterations predict prognosis and response to therapy in chronic lymphocytic leukemia (CLL), screening for TP53 mutations has an increasing role in patient management. TP53 direct sequencing is a time-consuming method, while the AmpliChip p53 Research Test is a novel non time-consuming microarray-based resequencing assay and queries Exons 2-11. We evaluated the impact of TP53 mutations on clinical outcome by analyzing 98 untreated CLL using the AmpliChip p53 Research Test and direct sequencing and performed microarrays analysis on TP53 mutated and/or deleted cases. The AmpliChip p53 Research Test detected 17 mutations in 14 patients (17.3%); a significant association between TP53 mutations and del(17p) was recorded. From a clinical standpoint, a higher percentage of mutation was found in CLL with unfavorable outcome (17.2% vs. 7.1% in progressive vs. stable cases). Detection of TP53 mutations by the AmpliChip p53 Research Test was associated with a significantly worse survival (P = 0.0002). Comparison of the array and direct sequencing tests showed that the p53 Research Test detected more mutations, although it failed to identify two microdeletions. Finally, microarrays analysis showed a more distinctive signature associated with del(17p) than with TP53 mutations, likely due to a concomitant gene dosage effect. The AmpliChip p53 Research Test is a straightforward method that bears prognostic value. This study confirms a high percentage of TP53 mutations in CLL with unfavorable outcome and a significant association between TP53 aberrations and del(17p). Finally, specific gene expression profiles are recognized for TP53 alterations. © 2011 Wiley-Liss, Inc. Source


Radio F.C.,San Giovanni Rotondo and CSS Mendel Institute | Bernardini L.,San Giovanni Rotondo and CSS Mendel Institute | Loddo S.,San Giovanni Rotondo and CSS Mendel Institute | Bottillo I.,San Giovanni Rotondo and CSS Mendel Institute | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

We report on a patient with mild mental retardation, prenatal onset growth retardation, cerebellar hypoplasia, and complex heart defect including: interventricular septal defect, patent foramen ovale, aortic coarctation, tricuspid valve insufficiency, mitral valve stenosis, and minor skeletal anomalies with hypoaplasia of the distal phalanges. ASNP-array analysis detected a de novo duplication of 17q23.2, encompassing the TBX2 gene. Animal models argue for a key role of Tbx2 during cardiac and limb development. Accordingly, we hypothesize that the heart malformation and mild digital anomalies found in this patient could be related to TBX2 gene overexpression, suggesting parallel consequences of TBX2 gene dosage imbalances in animals and in humans. © 2010 Wiley-Liss, Inc. Source


Ruggieri M.,University of Catania | Mastrangelo M.,University of Rome La Sapienza | Spalice A.,University of Rome La Sapienza | Mariani R.,University of Rome La Sapienza | And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

Anecdotal cases of polymicrogyria (PMG; a malformation of cortical development consisting of an excessive number of small gyri with abnormal lamination) in patients with neurofibromatosis type 1 (NF1) have been described; however, the cases were unilateral and had negative NF1 genetic testing. We describe an 11-year-old girl with NF1 manifesting as a complex epileptic syndrome, including partial seizures secondarily generalized and status epilepticus, who had in association, bilateral, asymmetrical (opercular and paracentral lobular) PMG. She had a 1-bp deletion (c.1862delC) in exon 12b of the NF1 gene. It is notable that, given the key role played by the NF1 gene product, neurofibromin, in normal brain development, and the relatively high frequency of other brain findings in NF1, there are not more NF1 cases with brain malformations manifesting as PMG. © 2011 Wiley-Liss, Inc. Source


Guarini A.,University of Rome La Sapienza | Marinelli M.,University of Rome La Sapienza | Tavolaro S.,University of Rome La Sapienza | Bellacchio E.,San Giovanni Rotondo and CSS Mendel Institute | And 11 more authors.
Haematologica | Year: 2012

Background: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cyto-genetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apopto-sis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval. © 2012 Ferrata Storti Foundation. Source

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