Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation

• Grant number: 14/11572-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: May 01, 2015
• End date: June 30, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maria Isabel de Souza Aranha Melaragno
• Grantee: Maria Isabel de Souza Aranha Melaragno
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: Chong Ae Kim
• Associated researchers: Ana Beatriz Alvarez Perez ; Carolina de Oliveira Gigek ; Diego Robles Mazzotti ; Gianna Maria Griz Carvalheira ; Janete Maria Cerutti ; Leslie Domenici Kulikowski ; Sang Won Han ; Síntia Iole Nogueira Belangero ; Taiza Stumpp Teixeira ; Vera de Freitas Ayres Meloni ; Vera Lúcia Gil da Silva Lopes
• Associated scholarship(s): 19/26175-8 - Investigation of mechanisms of formation of intrachromosomal rearrangements and its relation with the phenotype, BP.MS; 18/20618-2 - Search for genetic modifiers for congenital heart disease in the 22q11.2 Deletion Syndrome, BP.DR; 18/20633-1 - Investigation of the X-chromosome inactivation spread into autosomal regions in patients carrying unbalanced X-autosome translocations, BP.MS; + associated scholarships 19/07803-8 - Chromosomal rearrangements and its relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.IC; 19/00169-1 - Chromosomal rearrangements and its relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.PD; 18/11994-0 - Chromosomal rearrangements and its relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.PD; 18/08169-8 - Chromosomal rearrangements and its relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.IC; 16/22860-0 - Investigation of chromatin remodelling in balanced X-autosome translocations and its influence on phenotype, BP.DR; 17/07369-0 - Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.IC; 16/18781-7 - Pathogenic variants and expression of candidate genes to oculo-auriculo-vertebral spectrum (OAVS), BP.MS; 14/26768-5 - Investigation of patients with 22q11.2 deletion syndrome: Gene expression profile and evaluation of regulatory elements., BP.DR; 16/16075-8 - Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.IC; 16/09802-0 - Genomic imbalances consequences and formation mechanisms investigation in patients with congenital anomalies and intellectual disability, BP.PD; 15/08686-4 - Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation, BP.IC - associated scholarships

Abstract

A great challenge for cytogeneticists is to understand the genetic basis of the phenotypic variations and its implication for human diseases. Chromosomal rearrangements are an efficient tool for the investigation of the consequences of deletion, duplication or disruption of genes. This project contains three subprojects as follows: Subproject 1: Analysis of women with balanced X-autosome translocations whose breakpoints were previously determined by array painting. Lymphoblastoid cell lines will be established in order to study the reorganization of chromatin in the interphase nucleus and for gene function studies. Two genes will be analyzed in detail: (a) The AMMECR1 gene, disrupted in one of the patients, whose function is still unknown. AMMECR1's expression will be evaluated in different tissues of mouse embryos, in embryonic stem cells as well as in lymphoblastoid cell lines from both patient and control subject, with and without gene silencing, (b) The chimeric IL1RAPL1-ZNF61 gene, originated by the rearrangement in another patient with translocation, whose structure and consequences will be investigated. Subproject 2: In patients with 22q11.2 deletion syndrome with genomic losses of different sizes, the expression profile of genes and microRNAs will be analyzed; additionally, an investigation of allelic variants of genes in the deleted region will be performed. Subproject 3: In patients with congenital anomalies and intellectual disability, cytogenomic imbalances and their breakpoints will be investigated, and correlated to phenotype. The results obtained with these subprojects will allow a better comprehension of the etiology of clinical conditions as well as the role of gene variations and a better understanding of the molecular mechanisms for the formation of cytogenomic rearrangements. (AU)

Scientific publications

(24)

(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)

VICTÓRIA CABRAL SILVEIRA MONTEIRO DE GODOY; FERNANDA TEIXEIRA BELLUCCO; MILENY COLOVATI; HÉLIO RODRIGUES DE OLIVEIRA-JUNIOR; MARIANA MOYSÉS-OLIVEIRA; MARIA ISABEL MELARAGNO. Copy number variation (CNV) identification, interpretation, and database from Brazilian patients. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 4, 2020-11-13. (14/11572-8)

FAVILLA, BIANCA PEREIRA; MELONI, VERA AYRES; PEREZ, ANA BEATRIZ; MORETTI-FERREIRA, DANILO; DE SOUZA, DEISE HELENA; BELLUCCO, FERNANDA TEIXEIRA; MELARAGNO, MARIA ISABEL. Spread of X-chromosome inactivation into autosomal regions in patients with unbalanced X-autosome translocations and its phenotypic effects. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 185, n. 8, p. 2295-2305, AUG 2021. (14/11572-8, 19/21644-0)

BELLUCCO, FERNANDA T.; NUNES, NATALIA; COLOVATI, MILENY E. S.; MALINVERNI, ANDREA C. M.; CANELOI, THAMY P.; SOARES, MARIA F.; PEREZ, ANA B. A.; MELARAGNO, MARIA I.. Miller-Dieker Syndrome due to a 5.5-Mb 17p Deletion in a 17;Y Pseudodicentric Chromosome. Cytogenetic and Genome Research, v. 152, n. 1, p. 29-32, AUG 2017. (14/11572-8)

CERONI, J. R. M.; DUTRA, R. L.; HONJO, R. S.; LLERENA, JR., J. C.; ACOSTA, A. X.; MEDEIROS, P. F. V.; GALERA, M. F.; ZANARDO, E. A.; PIAZZON, F. B.; DIAS, A. T.; et al. A Multicentric Brazilian Investigative Study of Copy Number Variations in Patients with Congenital Anomalies and Intellectual Disability. SCIENTIFIC REPORTS, v. 8, SEP 6 2018. (09/53105-9, 09/53864-7, 14/11572-8, 08/58238-4, 12/25247-6)

MOYSES-OLIVEIRA, MARIANA; DI-BATTISTA, ADRIANA; ZAMARIOLLI, MALU; MELONI, VERA AYRES; BRAGAGNOLO, SILVIA; CHRISTOFOLINI, DENISE MARIA; STEINER, CARLOS EDUARDO; KOSYAKOVA, NADEZDA; LIEHR, THOMAS; REYMOND, ALEXANDRE; et al. Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes. European Journal of Human Genetics, v. 27, n. 5, p. 760-771, MAY 2019. (14/11572-8)

COLOVATI, MILENY E. S.; GROSSI, BEATRIZ M.; NUNES, GABRIELA D.; FOCK, RODRIGO A.; GUEDES, DULCE R.; MELARAGNO, MARIA I.; CERNACH, MIRLENE C. S. P.. Atypical Prader-Willi and 15q13.3 Microdeletion Syndromes in a Patient with an Unbalanced Translocation. Cytogenetic and Genome Research, v. 158, n. 4, p. 192-198, SEP 2019. (14/11572-8)

MELLO, C. B.; BUENO, O. F. A.; BENEDETTO, L. M.; PIMENTA, L. S. E.; TAKENO, S. S.; MELARAGNO, M. I.; MELONI, V. A.. Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, v. 63, n. 3, p. 225-232, MAR 2019. (14/11572-8)

ZAMARIOLLI, MALU; BURSSED, BRUNA; MOYSES-OLIVEIRA, MARIANA; COLOVATI, MILENY; BELLUCCO, FERNANDA TEIXEIRA DA SILVA; DOS SANTOS, LEONARDO CAIRES; ALVAREZ PEREZ, ANA BEATRIZ; BRAGAGNOLO, SILVIA; MELARAGNO, MARIA ISABEL. Novel MYT1 variants expose the complexity of oculo-auriculo-vertebral spectrum genetic mechanisms. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 185, n. 7, APR 2021. (14/11572-8, 11/23794-7)

BURSSED, BRUNA; ZAMARIOLLI, MALU; FAVILLA, BIANCA PEREIRA; MELONI, VERA AYRES; GOLONI-BERTOLLO, ENY MARIA; BELLUCCO, FERNANDA TEIXEIRA; MELARAGNO, MARIA ISABEL. Fold-back mechanism originating inv-dup-del rearrangements in chromosomes 13 and 15. Chromosome Research, v. 31, n. 1, p. 11-pg., 2023-02-24. (19/26175-8, 14/11572-8, 19/21644-0)

DI-BATTISTA, ADRIANA; MOYSES-OLIVEIRA, MARIANA; MELARAGNO, MARIA ISABEL. Genetics of premature ovarian insufficiency and the association with X-autosome translocations. Reproduction, v. 160, n. 4, p. 10-pg., 2020-10-01. (14/11572-8)

ZAMARIOLLI, MALU; DI-BATTISTA, ADRIANA; MOYSES-OLIVEIRA, MARIANA; DE MELLO, CLAUDIA B.; DE PAULA RAMOS, MARCO A.; LIEHR, THOMAS; MELARAGNO, I, MARIA. Disruption ofPCDH10andTNRC18Genes due to a Balanced Translocation. Cytogenetic and Genome Research, v. 160, n. 6, p. 321-328, JUL 2020. (14/11572-8)

SOARES, DIOGO C.; DANTAS, ANELISA G.; MATTA, MARINA C.; PASTORINO, ANTONIO C.; MELARAGNO, MARIA ISABEL; KULIKOWSKI, LESLIE; MONTENEGRO, MARILIA; KIM, CHONG A.; CARNEIRO-SAMPAIO, MAGDA; TORRES, LEURIDAN C.. Lymphoproliferative disorder with polyautoimmunity and hypogammaglobulinemia: An unusual presentation of 22q11.2 deletion syndrome. Clinical Immunology, v. 220, NOV 2020. (14/50489-9, 14/11572-8)

DI-BATTISTA, ADRIANA; MELONI, VERA AYRES; DA SILVA, MAGNUS DIAS; MOYSES-OLIVEIRA, MARIANA; MELARAGNO, MARIA ISABEL. Unusual X-Chromosome Inactivation Pattern in Patients with Xp11.23-p11.22 Duplication: Report and Review. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. 170, n. 12, p. 3271-3275, DEC 2016. (14/11572-8)

ZAMARIOLLI, MALU; COLOVATI, MILENY; MOYSES-OLIVEIRA, MARIANA; NUNES, NATALIA; DOS SANTOS, LEONARDO CAIRES; ALVAREZ PEREZ, ANA B.; BRAGAGNOLO, SILVIA; MELARAGNO, MARIA ISABEL. Rare single-nucleotide variants in oculo-auriculo-vertebral spectrum (OAVS). MOLECULAR GENETICS & GENOMIC MEDICINE, v. 7, n. 10, OCT 2019. (14/11572-8)

ZAMARIOLLI, MALU; DI-BATTISTA, ADRIANA; MOYSES-OLIVEIRA, MARIANA; DE MELLO, CLAUDIA B.; DE PAULA RAMOS, MARCO A.; LIEHR, THOMAS; MELARAGNO, MARIA, I. Disruption of PCDH10 and TNRC18 Genes due to a Balanced Translocation. Cytogenetic and Genome Research, v. 160, n. 6, p. 8-pg., 2020-07-01. (14/11572-8)

MOYSES-OLIVEIRA, MARIANA; CABRAL, VICTORIA; GIGEK, CAROLINA OLIVEIRA; DE CARVALHO CORREA, DEBORA CABRAL; DI-BATTISTA, ADRIANA; STUMPP, TAIZA; MELARAGNO, MARIA ISABEL. Search for appropriate reference genes for quantitative reverse transcription PCR studies in somite, prosencephalon and heart of early mouse embryo. Gene, v. 710, p. 148-155, AUG 20 2019. (14/11572-8)

BELLUCCO, FERNANDA T.; DE MELLO, CLAUDIA B.; MELONI, VERA A.; MELARAGNO, MARIA ISABEL. Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature. MOLECULAR GENETICS & GENOMIC MEDICINE, v. 7, n. 12, DEC 2019. (14/11572-8)

BELLUCCO, FERNANDA T.; DE OLIVEIRA-JUNIOR, HELIO RODRIGUES; GUILHERME, ROBERTA SANTOS; BRAGAGNOLO, SILVIA; ALVAREZ PEREZ, ANA B.; MELONI, VERA AYRES; MELARAGNO, I, MARIA. Deletion of Chromosome 13 due to Different Rearrangements and Impact on Phenotype. MOLECULAR SYNDROMOLOGY, v. 10, n. 3, p. 139-146, 2019. (14/11572-8)

MALINVERNI, ANDREA C. M.; YAMASHIRO COELHO, ERIKA M.; CHEN, KELIN; COLOVATI, MILENY E.; SOARES PINHO CERNACH, MIRLENE C.; BRAGAGNOLO, SILVIA; MELARAGNO, MARIA ISABEL. Deletion 21pterq22.11: Report of a Patient with Dysmorphic Features, Hypertonia, and Cafe-au-Lait Macules and Review of the Literature. Cytogenetic and Genome Research, v. 153, n. 2, p. 81-85, 2017. (14/11572-8)

MOYSES-OLIVEIRA, MARIANA; GIANNUZZI, GIULIANA; FISH, RICHARD J.; ROSENFELD, JILL A.; PETIT, FLORENCE; SOARES, MARIA DE FATIMA; KULIKOWSKI, LESLIE DOMENICI; DI-BATTISTA, ADRIANA; ZAMARIOLLI, MALU; XIA, FAN; et al. Inactivation of AMMECR1 is associated with growth, bone, and heart alterations. Human mutation, v. 39, n. 2, p. 281-291, FEB 2018. (14/11572-8)

BELLUCCO, FERNANDA T.; FOCK, RODRIGO A.; DE OLIVEIRA-JUNIOR, HELIO R.; PEREZ, ANA B.; MELARAGNO, MARIA I.. Complex Small Supernumerary Marker Chromosome Leading to Partial 4q/21q Duplications: Clinical Implication and Review of the Literature. Cytogenetic and Genome Research, v. 156, n. 4, p. 173-178, 2018. (14/11572-8)

DANTAS, ANELISA GOLLO; SANTORO, MARCOS LEITE; NUNES, NATALIA; DE MELLO, CLAUDIA BERLIM; EVANGELISTA PIMENTA, LARISSA SALUSTIANO; MELONI, VERA AYRES; QUEIROZ SOARES, DIOGO CORDEIRO; BELANGERO, SINTIA NOGUEIRA; CARVALHEIRA, GIANNA; KIM, CHONG AE; et al. Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome. Human Genetics, v. 138, n. 1, p. 93-103, JAN 2019. (14/11572-8, 14/26768-5)

CARVALHEIRA, GIANNA; MALINVERNI, ANDREA M.; MOYSES-OLIVEIRA, MARIANA; UETA, RENATA; CARDILI, LEONARDO; MONTEAGUDO, PATRICIA; MATHEZ, ANDREIA L. G.; VERRESCHI, IEDA T.; MALUF, MIGUEL A.; SHIDA, MARCIA E. F.; et al. The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene. JOURNAL OF THE ENDOCRINE SOCIETY, v. 3, n. 11, p. 2107-2113, NOV 2019. (14/11572-8, 11/20747-8, 12/00079-3, 14/06570-6)

MALINVERNI, ANDREA C. M.; COLOVATI, MILENY E.; PEREZ, ANA B. A.; CANELOI, THAMY P.; OLIVEIRA, JR., HELIO R.; KOSYAKOVA, NADEZDA; LIEHR, THOMAS; HAMID, AHMED B.; MELARAGNO, MARIA I.. Unusual Duplication in the Pericentromeric Region of Chromosome 9 in a Patient with Phenotypic Alterations. Cytogenetic and Genome Research, v. 150, n. 2, p. 100-105, 2016. (14/11572-8)