Banca de DEFESA: CARLOS VIRGÍLIO ROCHA DE SOUSA SILVA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : CARLOS VIRGÍLIO ROCHA DE SOUSA SILVA
DATE: 28/08/2023
TIME: 14:00
LOCAL: googlemeet
TITLE:

Sex Differentiation Disorders 46,XY: screening for pathogenic changes in a case series.

KEY WORDS:

DDS 46,XY, Etiological Diagnosis, Sequencing

PAGES: 35
BIG AREA: Ciências da Saúde
AREA: Medicina
SUMMARY:

INTRODUCTION: Human sexual development is a process that depends on the integral functioning of several genes and their proteins. Defects in any of these components can cause sex differentiation disorders (DSD). DSDs are congenital conditions in which genetic changes lead to the atypical development of chromosomal, gonadal and/or anatomical sex. The term DDS, adopted from the Consensus Statement on Management of Intersex Disorders, replaces terms considered pejorative and stigmatizing, such as hermaphroditism, pseudohermaphroditism, among others. DSDs may result from variations in genes involved in sexual determination and differentiation, resulting in disorders in gonadal and/or adrenal steroidogenesis, being classified into three groups, according to the karyotype: DDS 46,XY; DDS 46,XX; and DSD associated with chromosomal abnormalities. The DDS 46,XY group, the focus of this work, is characterized by its genetic complexity and phenotypic overlap, where the etiological clarification of these cases is carried out through molecular investigation in genes involved in the determination and differentiation of sex. OBJECTIVE: To perform molecular investigation in a series of cases of 46,XY DSD with no clear etiology. METHODS: From a sample of 58 cases of DDS 46,XY treated at the Clinical Genetics Service of the Professor Alberto Antunes University Hospital (HUPAA), 10 cases were selected for study. For the selection of samples, the following criteria were adopted: previous sequencing of the AR and SRD5A2 genes, no pathogenic changes in these genes and DNA sample available for study. The first stage of the molecular investigation consisted of the sequencing of the HSD17B3 gene by the Sanger method, carried out at the Laboratory of Human Molecular Genetics of HUPAA/UFAL. The second stage, for those cases in which no pathogenic changes in the HSD17B3 gene were identified, the next-generation sequencing (NGS) of 18 genes related to DDS 46,XY, was performed at the Large-Scale Sequencing Center of the Medical School of the University of São Paulo. RESULTS AND DISCUSSION: No pathogenic alterations in the HSD17B3 gene were identified in any of the selected cases. Through the NGS, changes were identified in four cases. In the case of DDSXY-03, hemizygosis of c.89G>T (p.Arg30Ile) alteration in the SRY gene was identified; in the case of DDSXY-04, heterozygosis of the c.565C>T alteration (p.Arg189Cys) in the FKBP4 gene was identified; in the case of DDSXY-07, the heterozygosis of the c.2389C>G (p.Leu797Val) alteration in the DHX37 gene was identified; and in the case of DDSXY-10, the heterozygosis of the c.250C>G alteration (p.Arg84Gly) in the NR5A1 gene was identified. The p.Arg84Gly alteration has not been previously described in the literature, the p.Leu797Val has been described as a variant of uncertain significance, and the p.Arg189Cys alteration has been reported in databases, without reference to the associated clinical condition. The p.Arg30Ile alteration has been described in cases of 46,XY gonadal dysgenesis. In silic predictive analyses revealed that the p.Arg189Cys; p.Leu797Val and p.Arg84Gly are deleterious. According to the literature, the frequency of patients diagnosed with DSD 46,XY without clarified etiology can vary between 33%-80%, even with advances in diagnostic elucidation tools. CONCLUSION: In this study, 40% of the sample presented alterations in genes that are fundamental in the determination/differentiation of sex and remain under investigation of the possible genotype-phenotype correlation. Already 60% remain under investigation aiming at the identification of pathogenic alterations that may justify the phenotype. The functional analysis of the alterations identified here are necessary for the correct genotype and phenotype correlation in each case. The results of this study reinforce the complexity of the etiological elucidation of DSD 46,XY.

BANKING MEMBERS:
Externo(a) à Instituição - Fernanda Caroline Soardi
Externo(a) ao Programa - 1121104 - DELIA MARIA DE MOURA LIMA HERRMANN
Externo(a) ao Programa - 3443233 - IRAMIRTON FIGUEREDO MOREIRA
Interno(a) - 2370894 - MICHELLE JACINTHA CAVALCANTE OLIVEIRA
Presidente - 1108003 - REGINALDO JOSE PETROLI