AMANDA DE MORAES NARCIZO
Projetos de Pesquisa
Unidades Organizacionais
FMUSP, Hospital das Clínicas, Faculdade de Medicina
6 resultados
Resultados de Busca
Agora exibindo 1 - 6 de 6
- Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum(2021) NAKAGUMA, Marilena; FERREIRA, Nathalia Garcia Bianchi Pereira; BENEDETTI, Anna Flavia Figueredo; MADI, Mariana Cotarelli; SILVA, Juliana Moreira; LI, Jun Z.; MA, Qianyi; OZEL, Ayse Bilge; FANG, Qing; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho de; CAMPER, Sally Ann; CARVALHO, Luciani R.We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (Delta Delta G = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.
- Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias(2022) BRAGA, B. L.; GOMES, N. L.; NISHI, M. Y.; FREIRE, B. L.; BATISTA, R. L.; FARIA JUNIOR, J. A. D.; FUNARI, M. F. A.; BENEDETTI, A. F. F.; NARCIZO, A. De Moraes; CARDOSO, L. Cavalca; LERARIO, A. M.; GUERRA-JUNIOR, G.; COSTA, E. M. F.; DOMENICE, S.; JORGE, A. A. L.; MENDONCA, B. B.Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.
- High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53(2020) BRONDANI, Vania Balderrama; MONTENEGRO, Luciana; LACOMBE, Amanda Meneses Ferreira; MAGALHAES, Breno Marchiori; NISHI, Mirian Yumie; FUNARI, Mariana Ferreira de Assis; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; SIQUEIRA, Sheila Aparecida Coelho; ZERBINI, Maria Claudia Nogueira; DENES, Francisco Tibor; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; ALMEIDA, Madson Queiroz; LERARIO, Antonio Marcondes; SOARES, Ibere Cauduro; FRAGOSO, Maria Candida Barisson VillaresAdrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for theMMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of alteredMMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.
- Targeted massively parallel sequencing panel to diagnose genetic endocrine disorders in a tertiary hospital(2022) NARCIZO, Amanda M.; CARDOSO, Lais C.; BENEDETTI, Anna F. F.; JORGE, Alexander A. L.; FUNARI, Mariana F. A.; BRAGA, Barbara L.; FRANCA, Monica M.; MONTENEGRO, Luciana R.; LERARIO, Antonio M.; NISHI, Mirian Y.; MENDONCA, Berenice B.Objectives: To analyze the efficiency of a multigenic targeted massively parallel sequencing panel related to endo-crine disorders for molecular diagnosis of patients assisted in a tertiary hospital involved in the training of medi-cal faculty.Material and methods: Retrospective analysis of the clinical diagnosis and genotype obtained from 272 patients in the Endocrine unit of a tertiary hospital was performed using a custom panel designed with 653 genes, most of them already associated with the phenotype (OMIM) and some candidate genes that englobes developmental, metabolic and adrenal diseases. The enriched DNA libraries were sequenced in NextSeq 500. Variants found were then classified according to ACMG/AMP criteria, with Varsome and InterVar.Results: Three runs were performed; the mean coverage depth of the targeted regions in panel sequencing data was 249x, with at least 96.3% of the sequenced bases being covered more than 20-fold. The authors identified 66 LP/P variants (24%) and 27 VUS (10%). Considering the solved cases, 49 have developmental dis-eases, 12 have metabolic and 5 have adrenal diseases.Conclusion: The application of a multigenic panel aids the training of medical faculty in an academic hospital by showing the picture of the molecular pathways behind each disorder. This may be particularly helpful in develop-mental disease cases. A precise genetic etiology provides an improvement in understanding the disease, guides decisions about prevention or treatment, and allows genetic counseling.
- 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.
- SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in Sao Paulo(2020) LERARIO, Antonio Marcondes; MOHAN, Dipika R.; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; NARCIZO, Amanda de Moraes; BENEDETTI, Anna Flavia Figueredo; OBA-SHINJO, Sueli Mieko; VITORINO, Aurelio Jose; SANTOS, Rogerio Alexandre Scripnic Xavier dos; JORGE, Alexander Augusto de Lima; ONUCHIC, Luiz Fernando; MARIE, Suely Kazue Nagahashi; MENDONCA, Berenice BilharinhoOBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Sao Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela