Distúrbios da diferenciação do sexo 46,XY: rastreamento de alterações patogênicas em uma série de casos

Abstract

Human sexual development is a process that depends on the normal functioning of several genes and their proteins. Defects in these components can lead to disorders of sexual development (DSD). DSDs are congenital conditions in which genetic alterations lead to atypical development of chromosomal, gonadal, and/or anatomical sexual development. The term DDS, adopted from the Consensus Statement on Management of Intersex Disorders, replaces terms considered pejorative and stigmatizing, such as hermaphroditism, pseudohermaphroditism, and others. DSD can result from variations in genes involved in sexual determination and differentiation, resulting in disorders in gonadal and/or adrenal steroidogenesis. DSD 46,XY; DSD 46.XX; and DSD associated with chromosomal abnormalities are the classifications of DSD. The DSD 46,XY, focus of this research, is characterized by genetic complexity and phenotypic overlap, where the etiological diagnosis is carried out through molecular investigation. AIM: Molecular investigation in 46,XY DSD cases. METHODS: Ten cases were selected for the study. For sample selection, the following criteria were adopted: prior sequencing of the AR and SRD5A2 genes, no pathogenic alterations identified in these genes, and DNA sample available for investigation. The first molecular analysis was the Sanger sequencing of the HSD17B3 gene. The second was the next-generation sequencing (NGS) of 18 genes related to 46,XY DSD. RESULTS AND DISCUSSION: The HSD17B3 sequencing was normal in all cases. The NGS revealed alterations in four cases: DDSXY-03 was identified as c.89G>T alteration hemizygosity in the SRY gene; in the DDSXY-04 case, the c.565C>T heterozygosity in the FKBP4 gene; the DDSXY-07 revealed the heterozygosity of c.2389C>G (p.Leu797Val) in the DHX37; and the heterozygosity c.250C>G alteration in NR5A1 in the DDSXY-10. The p.Arg84Gly alteration was not previously described in the literature, the p.Leu797Val was described as a variant of uncertain significance and the p.Arg189Cys alteration was reported in databases, without reference to the clinical condition associated. The p.Arg30Ile alteration has been described in 46,XY gonadal dysgenesis cases. The results of in silico predictive analyses of p.Arg189Cys; p.Leu797Val and p.Arg84Gly alterations were deleterious. According to the literature, 33%- 80% of patients diagnosed with 46,XY DSD remain without etiology elucidated. CONCLUSION: In this study, 40% of the participants presented alterations in genes that are fundamental in the determination/differentiation of sexual development and remain under investigation of the possible genotype-phenotype correlation. Already 60% remain under investigation aimed at identifying pathogenic changes that may justify the phenotype. Functional analysis of the alterations here identified is necessary for the correct genotypephenotype correlation. These results reinforce the complexity of the etiologicalelucidation of 46,XY DSD.