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Impact of genetic variants on genomic stability and their effects on the phenotype

Grant number: 19/21644-0
Support Opportunities:Research Projects - Thematic Grants
Duration: November 01, 2020 - October 31, 2025
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:Claudia Berlim de Mello ; Fernanda Teixeira da Silva Bellucco ; Iscia Teresinha Lopes Cendes ; Mariana Moysés Oliveira ; Paulo Bandiera Paiva ; Vera Lúcia Gil da Silva Lopes
Associated grant(s):22/02202-9 - Multi-user equipment approved in grant 2019/21644-0: SeqStudio" Genetic Analyzer System, AP.EMU
Associated scholarship(s):23/10217-9 - Investigation of patients with phenotypic features suggestive of cytogenomic alterations, BP.MS
23/17803-0 - IMPACT OF GENETIC VARIANTS ON GENOMIC STABILITY AND THEIR EFFECTS ON THE PHENOTYPE, BP.IC
23/10945-4 - IMPACT OF GENETIC VARIANTS ON GENOMIC STABILITY AND THEIR EFFECTS ON THE PHENOTYPE, BP.IC
+ associated scholarships 22/03989-2 - Complex rearrangements: mechanisms of formation and relation with the phenotype, BP.DR
22/11841-5 - IMPACT OF GENETIC VARIANTS ON GENOMIC STABILITY AND THEIR EFFECTS ON THE PHENOTYPE, BP.IC
22/09582-1 - Assessment of mitotic and genomic stability of lymphoblastoid cells from patients with Cornelia de Lange Syndrome, BP.DD
21/12996-0 - Assessment of mitotic and genomic stability of lymphoblastoid cells from patients with Cornelia de Lange Syndrome, BP.MS
22/03428-0 - Search for genetic variants with pathogenic potential in patients with a characteristic phenotype of coesinopathies focusing on the Cornelia de Lange Syndrome, BP.DD
22/00829-4 - Impact of genetic variants on genomic stability and their effects on the phenotype, BP.IC
20/15167-1 - Neuropsychological and social cognition profile in the 22q11 delection syndrome and its relevance for the risk of psychosis: a comparative study with a first psychotic episode sample, BP.MS
20/16422-5 - Characterization of the inactivation of autosomal sequences in patients with unbalanced X-autosome translocations, BP.DR - associated scholarships

Abstract

The investigation of cytogenomic and molecular alterations through refined and powerful research methodologies has been allowing the characterization of genetic variants at a higher resolution, enabling a better understanding of their mechanisms of formation and their impact on the phenotype. The current project proposes the use of innovative approaches, including several types of next-generation sequencing, bioinformatics tools, and other techniques that can grant better insight into genome architecture and its clinical consequences. The present research project contains three subprojects, harboring different Studies as follows: subproject 1 refers to the "Investigation of balanced and unbalanced structural rearrangements involving the X chromosome". In patients with unbalanced X-autosome translocations, both the spread of X-chromosome inactivation into autosomal sequences and the impact of autosomal silencing on the patients' phenotype will be investigated (study 1). In women carrying different X-autosome balanced translocations, and phenotypic alterations, the breakpoints will be mapped to identify gene disruptions in the derivative X whose association with a skewed inactivation of the normal X may result in the lack of functional copies of those genes with clinical consequences (study 2). In women with balanced X-autosome translocations, and premature ovarian failure, without gene disruptions associated with the phenotype, the chromatin reorganization caused by the rearrangement will be explored since the position effect is one of the main hypotheses to explain gonadal dysfunction in these patients (study 3). Subproject 2 refers to the "Investigation of rare autosomal structural rearrangements of scientific interest". Patients with intrachromosomal rearrangements will be evaluated, focusing on breakpoint sequencing to elucidate their mechanisms of formation and their impact on the phenotype (study 1). Other patients with sundry rearrangements will also be evaluated, focusing on determining the pathogenic mechanisms of the rearrangements and their relationship with the phenotype (study 2). Subproject 3, on the other hand, refers to the "Investigation of patients with 22q11.2 deletion syndrome" and harbors different approaches, with a focus on phenotypic variability that the patients present. Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) will be analyzed to better understand the genetic modifiers that can impact the patients' phenotypes, especially cardiac malformation and scoliosis. Bioinformatics tools, including machine learning, will be employed (study 1). Through the sequencing of a panel of candidate genes, the role of genetic variants and their impact on mRNA and miRNA expressions will be evaluated (study 2). Structural variants in low copy repeats (LCRs) in the 22q11.2 region will also be investigated to identify their different genomic compositions that may predispose the region to rearrangements (study 3). In general, by investigating structural rearrangements, the subprojects proposed herein compose a single unity directed towards a better comprehension of the genome. Thus, their development will be crucial to increase our knowledge of the impact that genetic variants may cause on the phenotype as well as plasticity and stability of our genome. (AU)

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Scientific publications (9)
(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)
NUNES, NATALIA; ZAMARIOLLI, MALU; DANTAS, ANELISA GOLLO; COLA, PAULA; DE AGOSTINHO JUNIOR, FRANCISCO; PIAZZON, FLAVIA BALBO; MELONI, VERA AYRES; MELARAGNO, MARIA ISABEL. CEDNIK syndrome in a Brazilian patient with compound heterozygous pathogenic variants. EUROPEAN JOURNAL OF MEDICAL GENETICS, v. 65, n. 3, p. 4-pg., . (19/21644-0)
ZAMARIOLLI, M.; DANTAS, A. G.; NUNES, N.; MOYSES-OLIVEIRA, M.; SGARDIOLI, I. C.; SOARES, D. C. Q.; GIL-DA-SILVA-LOPES, V. L.; KIM, C. A.; MELARAGNO, M. I.. Phenotypic heterogeneity in 22q11.2 deletion syndrome: Copy Number Variants as genetic modifiers for congenital heart disease in a Brazilian cohort. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, v. N/A, p. 9-pg., . (19/21644-0, 18/20618-2)
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, . (14/11572-8, 19/21644-0)
OLIVATI, CAROLINE; FAVILLA, BIANCA PEREIRA; FREITAS, ERIKA LOPES; SANTOS, BIBIANA; MELARAGNO, MARIA ISABEL; MELONI, VERA AYRES; PIAZZON, FLAVIA. Allan-Herndon-Dudley syndrome in a female patient and related mechanisms. MOLECULAR GENETICS AND METABOLISM REPORTS, v. 31, p. 4-pg., . (19/21644-0)
KOZEL, BETH A.; BARAK, BOAZ; KIM, CHONG AE; MERVIS, CAROLYN B.; OSBORNE, LUCY R.; PORTER, MELANIE; POBER, BARBARA R.. Williams syndrome. NATURE REVIEWS DISEASE PRIMERS, v. 7, n. 1, . (19/21644-0)
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., . (19/26175-8, 14/11572-8, 19/21644-0)
ZAMARIOLLI, MALU; AUWERX, CHIARA; SADLER, MARIE C.; VAN DER GRAAF, ADRIAAN; LEPIK, KAIDO; SCHOELER, TABEA; MOYSES-OLIVEIRA, MARIANA; DANTAS, ANELISA G.; MELARAGNO, MARIA ISABEL; KUTALIK, ZOLTAN. The impact of 22q11.2 copy-number variants on human traits in the general population. American Journal of Human Genetics, v. 110, n. 2, p. 14-pg., . (20/11241-2, 19/21644-0)
FAVILLA, BIANCA PEREIRA; BURSSED, BRUNA; YAMASHIRO COELHO, ERIKA MITIE; PEREZ, ANA BEATRIZ ALVAREZ; DE FARIA SOARES, MARIA DE FATIMA; MELONI, VERA AYRES; BELLUCCO, FERNANDA TEIXEIRA; MELARAGNO, MARIA ISABEL. Minimal Critical Region and Genes for a Typical Presentation of Langer-Giedion Syndrome. Cytogenetic and Genome Research, v. N/A, p. 9-pg., . (19/21644-0)
BURSSED, BRUNA; ZAMARIOLLI, MALU; BELLUCCO, FERNANDA TEIXEIRA; MELARAGNO, MARIA ISABEL. Mechanisms of structural chromosomal rearrangement formation. MOLECULAR CYTOGENETICS, v. 15, n. 1, p. 15-pg., . (19/21644-0)

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