NATHALIA LISBOA ROSA ALMEIDA GOMES
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
5 resultados
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- 46,XY disorder of sex development (DSD) due to 17 beta-hydroxysteroid dehydrogenase type 3 deficiency(2017) MENDONCA, Berenice B.; GOMES, Nathalia Lisboa; COSTA, Elaine M. F.; INACIO, Marlene; MARTIN, Regina M.; NISHI, Mirian Y.; CARVALHO, Filomena Marino; TIBOR, Francisco Denes; DOMENICE, Sorahia17 beta-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17 beta-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17 beta-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5 alpha-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17 beta-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review-the previously reported cases of 17 beta-HSD3 deficiency adding our own cases. (C) 2016 Published by Elsevier Ltd.
- WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease(2022) FERRARI, M. T. M.; WATANABE, A.; SILVA, T. E. Da; GOMES, N. L.; BATISTA, R. L.; NISHI, M. Y.; PAULA, L. C. P. De; COSTA, E. C.; COSTA, E. M. F.; CUKIER, P.; ONUCHIC, L. F.; MENDONCA, B. B.; DOMENICE, S.Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs∗14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.
- Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development(2022) GOMES, Nathalia Lisboa; BATISTA, Rafael Loch; NISHI, Mirian Y.; LERARIO, Antonio Marcondes; SILVA, Thatiana E.; NARCIZO, Amanda de Moraes; BENEDETTI, Anna Flavia Figueredo; FUNARI, Mariana Ferreira de Assis; FARIA JUNIOR, Jose Antonio; MORAES, Daniela Rodrigues; QUINTAO, Lia Mesquita Lousada; MONTENEGRO, Luciana Ribeiro; FERRARI, Maria Teresa Martins; JORGE, Alexander A.; ARNHOLD, Ivo J. P.; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoContext Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). Objective To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. Design/patients 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. Results Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. Conclusions The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD.
- Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development(2018) SPROLL, Patrick; EID, Wassim; GOMES, Camila R.; MENDONCA, Berenice B.; GOMES, Nathalia L.; COSTA, Elaine M. -F.; BIASON-LAUBER, AnnaBackgroundOne of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders/differences of sex development (DSD). Chromobox protein homolog 2 (CBX2) has two distinct isoforms, CBX2.1 and CBX2.2: the role of CBX2.1 in DSD has been previously established, yet to date the function of the smaller isoform CBX2.2 remains unknown. MethodsThe genomic DNA of two 46,XY DSD patients was analysed using whole exome sequencing. Furthermore, protein/DNA interaction studies were performed using DNA adenine methyltransferase identification (DamID) to identify putative binding partners of CBX2. Finally, invitro functional studies were used to elucidate the effect of wild-type and variant CBX2.2 on selected downstream targets. ResultsHere, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT). We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad. ConclusionOur study indicates a distinct function of the shorter form of CBX2 and by identifying several of its unique targets, can advance our understanding of DSD pathogenesis and ultimately DSD diagnosis and management.
- A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant(2019) GOMES, Nathalia L.; PAULA, Leila C. P. de; SILVA, Juliana M.; SILVA, Thatiana E.; LERARIO, Antonio M.; NISHI, Mirian Y.; BATISTA, Rafael L.; FARIA JUNIOR, Jose A. D.; MORAES, Daniela; COSTA, Elaine M. F.; HEMESATH, Tatiana P.; GUARAGNA-FILHO, Guilherme; LEITE, Julio C. L.; CARVALHO, Clarissa G.; DOMENICE, Sorahia; COSTA, Eduardo C.; MENDONCA, Berenice B.Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.