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Submicroscopic genomic imbalances associated with specific congenital abnormalities and mental deficiency phenotypes


Comparative genomic hybridization to arrays, or array-CGH (aCGH) is a technique that allows genome-wide investigation of gains and losses of DNA sequences with a resolution at least 2 order of magnitude higher than classical cytogenetics. We first implemented aCGH at the Institute of Bioscience of University of São Paulo (IBUSP) in 2004 with the support of the CEPID - Human Genome Research Center. Over the last 4 years we investigated submicroscopic copy number alterations in about 400 families involving individuals with mental impairment and/or congenital abnormalities; cryptic chromosome alterations were detected in 17-30% of the patients dependent upon clinical criteria. Two types of benefit resulted from this work, namely: (a) determining recurrence risks and offering genetic counseling to these families; (b) 20 peer reviewed publications contributing to collaborative mapping of specific disorders and description of new syndromes, several of them involving international groups. The microarrays used during this period had been produced by the coordinator of this project C. Rosenberg while she was a faculty member at Leiden University (the Netherlands), and were donated free of charge to the University of São Paulo; these arrays had BACs as targets and an average resolution of 1 Mb. However, the BAC-arrays are now being replaced by oligonucleotide arrays, which have a much higher resolution and lower costs. In the following proposal, we continue implementation of the oligoarray using a high resolution commercially available and reliable platform, to investigate new patient groups totaling 400 patients and 200 controls. The PIs and collaborative researchers represent Brazilian reference centers for specific clinical phenotypes, namely: müllerian anomalies, Silver-Russel syndrome, X-linked mental deficiency, and pediatric cancers associated with further congenital defects. An important component of this project involves several international collaborations, namely: (a) a collaboration with Dr. John Crolla, National Genetics Reference Laboratory, Wessex, UK, who coordinates a European consortium for users of standardized aCGH platform for diagnosing mental deficiency and congenital abnormalities; (b) both Drs. Crolla and C. Rosenberg are part of an international consortium for aCGH standardization in clinical studies, which is subsidized by the National Institute of Health (NIH, USA) and coordinated by Dr. David Ledbetter, from Atlanta University; (c) C. Rosenberg is participating in the international consortium DECIPHER - Database of Chromosomal Imbalances and Phenotype in humans using Ensembl Resources (, in which submicroscopic alterations detected in patients with altered phenotypes is compiled and made available on line. This project is a collaboration between the IBUSP and the Cancer Hospital AC Camargo. The coordinator of this project, who is at present researcher at the Cancer Hospital AC Camargo, has been approved in an open selection for a faculty position in the IBUSP, and is waiting for processing the documents to start in the new position. The researcher then will be employed by USP and remain as collaborator of the Cancer Hospital, which will not interfere in carrying out the project. (AU)

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Scientific publications (23)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MASCHIETTO, MARIANA; RODRIGUES, TATIANE CRISTINA; KASHIWABARA, ANDRE YOSHIAKI; SOUZA DE ARAUJO, ERICA SARA; MARQUES AGUIAR, TALITA FERREIRA; LIMA DA COSTA, CECILIA MARIA; DA CUNHA, ISABELA WERNECK; VASQUES, LUCIANA DOS REIS; CYPRIANO, MONICA; BRENTANI, HELENA; et al. DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations. ONCOTARGET, v. 8, n. 58, p. 97871-97889, . (15/06281-7, 09/00898-1, 16/04785-0, 13/08028-1, 11/24007-9)
BONALDI, ADRIANO; KASHIWABARA, ANDRE; DE ARAUJO, ERICA S.; PEREIRA, LYGIA V.; PASCHOAL, ALEXANDRE R.; ANDOZIA, MAYRA B.; VILLELA, DARINE; RIVAS, MARIA P.; SUEMOTO, CLAUDIA K.; PASQUALUCCI, CARLOS A.; et al. Mining Novel Candidate Imprinted Genes Using Genome-Wide Methylation Screening and Literature Review. EPIGENOMES, v. 1, n. 2, . (13/07480-8, 09/00898-1, 13/08028-1)
VICTORINO KREPISCHI, ANA CRISTINA; CAPELLI, LEONARDO PIRES; SILVA, AMANDA GONCALVES; SOUZA DE ARAUJO, ERICA SARA; PEARSON, PETER LEES; HECK, BENJAMIN; LIMA DA COSTA, CECILIA MARIA; DE CAMARGO, BEATRIZ; ROSENBERG, CARLA. Large germline copy number variations as predisposing factor in childhood neoplasms. FUTURE ONCOLOGY, v. 10, n. 9, p. 1627-1633, . (09/02058-0, 09/00898-1, 08/57887-9, 13/08028-1)
CANTON, ANA P. M.; COSTA, SILVIA S.; RODRIGUES, TATIANE C.; BERTOLA, DEBORA R.; MALAQUIAS, ALEXSANDRA C.; CORREA, FERNANDA A.; ARNHOLD, IVO J. P.; ROSENBERG, CARLA; JORGE, ALEXANDER A. L.. Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 171, n. 2, p. 253-262, . (09/00898-1, 13/03236-5)
VILLELA, DARINE; SCHLESINGER, DAVID; SUEMOTO, CLAUDIA K.; GRINBERG, LEA T.; ROSENBERG, CARLA. A microdeletion in Alzheimer's disease disrupts NAMPT gene. JOURNAL OF GENETICS, v. 93, n. 2, p. 535-537, . (09/00898-1, 10/15503-0)
CAPELLI, LEONARDO P.; KREPISCHI, C. V.; GURGEL-GIANNETTI, JULIANA; MENDES, MIRIAN FABIOLA S.; RODRIGUES, TATIANE; VARELA, MONICA C.; KOIFFMANN, CELIA P.; ROSENBERG, CARLA. Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency. EUROPEAN JOURNAL OF MEDICAL GENETICS, v. 55, n. 2, p. 132-134, . (09/00898-1, 98/14254-2)
DANTAS, VITOR G. L.; FREITAS, ERIKA L.; DELLA-ROSA, VALTER A.; LEZIROVITZ, KARINA; DE MORAES, ANA MARIA S. M.; RAMOS, SILVIA B.; OITICICA, JEANNE; ALVES, LEANDRO U.; PEARSON, PETER L.; ROSENBERG, CARLA; et al. Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family. INTERNATIONAL JOURNAL OF AUDIOLOGY, v. 54, n. 9, p. 593-598, . (09/00898-1, 09/05620-1, 98/14254-2)
DARINE VILLELA; LILIAN KIMURA; DAVID SCHLESINGER; AMANDA GONÇALVES; PETER L. PEARSON; CLAUDIA K. SUEMOTO; CARLOS PASQUALUCCI; ANA CRISTINA KREPISCHI; LEA T. GRINBERGAND; CARLA ROSENBERG. Germline DNA copy number variation in individuals with Argyrophilic grain disease reveals CTNS as a plausible candidate gene. GENETICS AND MOLECULAR BIOLOGY, v. 36, n. 4, p. 498-501, . (09/00898-1)
RODRIGUES, TATIANE CRISTINA; FIDALGO, FELIPE; LIMA DA COSTA, CECILIA MARIA; FERREIRA, ELISA NAPOLITANO; DA CUNHA, ISABELA WERNECK; CARRARO, DIRCE MARIA; VICTORINO KREPISCHI, ANA CRISTINA; ROSENBERG, CARLA. Upregulated genes at 2q24 gains as candidate oncogenes in hepatoblastomas. FUTURE ONCOLOGY, v. 10, n. 15, p. 2449-2457, . (06/00054-0, 09/00898-1, 13/08028-1, 11/24007-9)
SIMIONI, MILENA; VIEIRA, TARSIS PAIVA; SGARDIOLI, ILARIA CRISTINA; FREITAS, ERIKA LOPES; ROSENBERG, CARLA; MAURER-MORELLI, CLAUDIA VIANNA; LOPES-CENDES, ISCIA; FETT-CONTE, AGNES CRISTINA; GIL-DA-SILVA-LOPES, VERA LUCIA. Insertional translocation of 15q25-q26 into 11p13 and duplication at 8p23.1 characterized by high resolution arrays in a boy with congenital malformations and aniridia. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 158A, n. 11, p. 2905-2910, . (09/00898-1, 08/10596-0)
KREPISCHI‚ A.C.V.; ACHATZ‚ M.I.W.; SANTOS‚ E.M.M.; COSTA‚ S.S.; LISBOA‚ B.C.G.; BRENTANI‚ H.; SANTOS‚ T.M.; GONÇALVES‚ A.; NÓBREGA‚ A.F.; PEARSON‚ P.L.; et al. Germline DNA copy number variation in familial and early-onset breast cancer. BREAST CANCER RESEARCH, v. 14, n. 1, p. R24, . (09/00898-1, 08/57887-9)
FONSECA, A. C. S.; BONALDI, A.; COSTA, S. S.; FREITAS, M. R.; KOK, F.; VIANNA-MORGANTE, A. M.. PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus-Merzbacher disease in a girl. Clinical Genetics, v. 83, n. 2, p. 169-174, . (09/03480-8, 09/00898-1, 98/14254-2)
VICTORINO KREPISCHI, ANA CRISTINA; PEARSON, PETER LEES; ROSENBERG, CARLA. Germline copy number variations and cancer predisposition. FUTURE ONCOLOGY, v. 8, n. 4, p. 441-450, . (09/00898-1, 08/57887-9)
BONALDI, ADRIANO; MAZZEU, JULIANA F.; COSTA, SILVIA S.; HONJO, RACHEL S.; BERTOLA, DEBORA R.; ALBANO, LILIAN M. J.; FURQUIM, ISABEL M.; KIM, CHONG A.; VIANNA-MORGANTE, ANGELA M.. Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 155A, n. 10, p. 2479-2483, . (09/00898-1, 09/03341-8, 98/14254-2)
VICTORINO KREPISCHI, ANA CRISTINA; KNIJNENBURG, JEROEN; BERTOLA, DEBORA ROMEO; KIM, CHONG AE; PEARSON, PETER LEES; BIJLSMA, EMILIA; SZUHAI, KAROLY; KOK, FERNANDO; VIANNA-MORGANTE, ANGELA MARIA; ROSENBERG, CARLA. Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy. Epilepsia, v. 51, n. 12, p. 2457-2460, . (09/00898-1, 98/14254-2)
LINHARES, NATALIA D.; SVARTMAN, MARTA; RODRIGUES, TATIANE C.; ROSENBERG, CARLA; VALADARES, EUGENIA R.. Subtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations. EUROPEAN JOURNAL OF MEDICAL GENETICS, v. 58, n. 5, p. 310-318, . (09/00898-1)
SILVA, AMANDA G.; KREPISCHI, ANA C. V.; PEARSON, PETER L.; HAINAUT, PIERRE; ROSENBERG, CARLA; ACHATZ, MARIA ISABEL. The profile and contribution of rare germline copy number variants to cancer risk in Li-Fraumeni patients negative for TP53 mutations. ORPHANET JOURNAL OF RARE DISEASES, v. 9, . (09/00898-1, 08/57887-9)
VILLELA, DARINE; SUEMOTO, CLAUDIA K.; PASQUALUCCI, CARLOS A.; GRINBERG, LEA T.; ROSENBERG, CARLA. Do Copy Number Changes in CACNA2D2, CACNA2D3, and CACNA1D Constitute a Predisposing Risk Factor for Alzheimer's Disease?. FRONTIERS IN GENETICS, v. 7, . (09/00898-1, 10/15503-0, 13/08028-1)
FONTES, MARSHALL I. B.; SANTOS, ANA P.; MOLCK, MIRIAM C.; SIMIONI, MILENA; NASCIMENTO, DIOGO L. L.; ANDRADE, ANA K. M.; ROSENBERG, CARLA; KREPISCHI, ANA C. V.; APPENZELLER, SIMONE; MONLLEO, ISABELLA L.; et al. Genotype-Phenotype Correlation of 16p13.3 Terminal Duplication and 22q13.33 Deletion: Natural History of a Patient and Review of the Literature. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 170, n. 3, p. 766-772, . (09/00898-1, 12/10071-0, 12/51799-6, 13/08028-1)
VILLELA, DARINE; RAMALHO, RODRIGO F.; SILVA, ADERBAL R. T.; BRENTANI, HELENA; SUEMOTO, CLAUDIA K.; PASQUALUCCI, CARLOS AUGUSTO; GRINBERG, LEA T.; KREPISCHI, ANA C. V.; ROSENBERG, CARLA. Differential DNA Methylation of MicroRNA Genes in Temporal Cortex from Alzheimer's Disease Individuals. NEURAL PLASTICITY, . (09/00898-1, 10/15503-0, 13/08028-1)
LINHARES, NATALIA D.; VALADARES, EUGENIA R.; DA COSTA, SILVIA S.; ARANTES, RODRIGO R.; DE OLIVEIRA, LUIZ ROBERTO; ROSENBERG, CARLA; VIANNA-MORGANTE, ANGELA M.; SVARTMAN, MARTA. Inherited Xq13.2-q21.31 duplication in a boy with recurrent seizures and pubertal gynecomastia: Clinical, chromosomal and aCGH characterization. META GENE, v. 9, p. 185-190, . (09/00898-1, 98/14254-2)
HOMMA, THAIS K.; KREPISCHI, ANA C. V.; FURUYA, TATIANE K.; HONJO, RACHEL S.; MALAQUIAS, ALEXSANDRA C.; BERTOLA, DEBORA R.; COSTA, SILVIA S.; CANTON, ANA P.; ROELA, ROSIMEIRE A.; FREIRE, BRUNA L.; et al. Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause. Hormone Research in Paediatrics, v. 89, n. 1, p. 13-21, . (15/26980-7, 09/00898-1, 13/03236-5, 13/08028-1)

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