MARIANA FERREIRA DE ASSIS FUNARI
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma(2023) FAGUNDES, Gustavo F. C.; FREITAS-CASTRO, Felipe; SANTANA, Lucas S.; AFONSO, Ana Caroline F.; PETENUCI, Janaina; FUNARI, Mariana F. A.; GUIMARAES, Augusto G.; LEDESMA, Felipe L.; PEREIRA, Maria Adelaide A.; VICTOR, Carolina R.; FERRARI, Marcela S. M.; COELHO, Fernando M. A.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
- Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature(2022) ANDRADE, Nathalia Liberatoscioli Menezes; FUNARI, Mariana Ferreira de Assis; MALAQUIAS, Alexsandra Christianne; COLLETT-SOLBERG, Paulo Ferrez; GOMES, Nathalia L. R. A.; SCALCO, Renata; DANTAS, Naiara Castelo Branco; REZENDE, Raissa C.; TIBURCIO, Angelica M. F. P.; SOUZA, Micheline A. R.; FREIRE, Bruna L.; V, Ana C. Krepischi; LONGUI, Carlos Alberto; LERARIO, Antonio Marcondes; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.; VASQUES, Gabriela AndradeObjectiveMost children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS. Design and methodsWe selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools. ResultsWe identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN (n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11 (n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS <= or > -3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children. ConclusionA multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.
conferenceObject IDENTIFICATION OF NEW GENETIC MODIFIERS OF THE PHENOTYPE IN SHOX HAPLOINSUFFICIENCY(2023) DANTAS, N. C. B.; FUNARI, M. F.; ANDRADE, N. L. M.; REZENDE, R. C.; CELLIN, L. P.; LERARIO, A. M.; NISHI, M. Y.; MENDONCA, B. B.; JORGE, A. De LimaconferenceObject Evaluation of the trabecular bone score in 35 children and adults with X-Linked hypophosphatemic rickets(2023) COLARES NETO, Guido de Paula; PEREIRA, Rosa Maria Rodrigues; ALVARENGA, Jackeline Couto; TAKAYAMA, Liliam; FUNARI, Mariana Ferreira de Assis; MARTIN, Regina MatsunagaconferenceObject Girls with short statute and Xp22;Yq11 translocation: should a prophylactic gonadectomy be recommended ?(2023) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; CELLIN, Laurana P.; CRISOSTOMO, Lindiane G.; SCALCO, Renata C.; JORGE, Alexander A. L.- 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.
conferenceObject The pre- and postnatal influence of androgens in the psychosexual development of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency(2023) BATISTA, Rafael Loch; INACIO, Marlene; MADUREIRA, Guiomar; MIRANDA, Mirela; GOMES, Larissa; RODRIGUES, Andresa; FUNARI, Mariana; BACHEGA, Tania; MENDONCA, Berenice Bilharinho- Evaluation of the trabecular bone score in 35 children and adults with X-linked hypophosphatemic rickets(2023) COLARES NETO, Guido de Paula; PEREIRA, Rosa Maria Rodrigues; ALVARENGA, Jackeline Couto; TAKAYAMA, Liliam; FUNARI, Mariana Ferreira de Assis; MARTIN, Regina MatsunagaIntroduction The aim of this study is to evaluate and compare the trabecular bone scores (TBSs) of 11 children and 24 adults with X-linked hypophosphatemic rickets (XLH) and non-XLH subjects from a tertiary center.Materials and methods The areal bone mineral density at the lumbar spine (LS-aBMD) and LS-aBMD Z score were analyzed by dual-energy X-ray absorptiometry. The bone mineral apparent density (BMAD) and LS-aBMD Z score adjusted for height Z score (LS-aBMD-HAZ) were calculated. The TBS was determined using TBS iNsight software based on DXA images from the Hologic QDR 4500 device.ResultsThe XLH patients exhibited a higher mean LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). LS-aBMD-HAZ and BMAD were greater in the XLH children than those in their corresponding non-XLH subjects (p < 0.01 and p = 0.02), and the XLH children trended toward a greater TBS (p = 0.06). The XLH adults had a higher LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). When stratified by metabolic status according to the serum values of bone formation markers, compensated adult patients had a higher LS-aBMD Z score, BMAD, and TBS than non-XLH subjects (p < 0.01). Noncompensated patients had higher LS-aBMD Z scores and BMAD results than non-XLH subjects. However, TBS values did not differ statistically significantly between those groups (p = 0.45).ConclusionThe higher LS-aBMD Z score, BMAD, and TBS result in the XLH patients compared to non-XLH subjects indicates an increased amount of trabecular bone within the lumbar spine, regardless of extraskeletal calcifications.
conferenceObject A prospective genetic analysis of children with idiopathic short stature (ISS) using whole-exome sequencing (WES): first results(2023) CELLIN, Laurana P.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; SOUZA, Vinicius de; DANTAS, Naiara C. B.; QUEDAS, Elisangela P. S.; FUNARI, Mariana F. A.; VASQUES, Gabriela A.; SCALCO, Renata C.; MALAQUIAS, Alexsandra A. C.; JORGE, Alexander A. L.- Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability(2023) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; CELLIN, Laurana P.; ALVES, Cresio; CRISOSTOMO, Lindiane G.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice; SCALCO, Renata C.; JORGE, Alexander A. L.Objective Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature.Design and methods We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants.Results We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04).Conclusion In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.