Systematic approach and diagnosis of 46, XY differences of sex development: molecular investigation and APP development

• Grant number: 23/10426-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2023
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Berenice Bilharinho de Mendonça
• Grantee: Maria Jimena Chafloque Mesia
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/26780-9 - Molecular and epigenetic research on Differences in Sexual Development (DSD): impact of scientific diffusion on the relationship between science and society, AP.TEM

Abstract

Differences of Sex Development (DSD) are a group of congenital conditions defined by a discordance of chromosomal, gonadal and/or anatomical sex. 46,XY DSD are a subgroup characterized by a wide phenotype, varying from a micropenis to atypical or female external genitalia, with or without Mullerian derivatives, due to an inadequate testosterone and dihydrotestosterone synthesis or lack of their action. Diagnosis of 46,XY DSD is challenging, only using clinical tools the etiology is not often identified. The use of massively parallel sequencing (MPS) technologies in DSD patients has help identify new genes and variants responsible of the phenotype. Using a target panel the diagnosis reaches up to 43%. Diagnosis accuracy improves when using whole exome sequencing, identification of pathogenic or likely pathogenic variants is obtain in 50 to 78% of studied cases. The present study aims to identify molecular etiology of 46,XY DSD patients of undetermined etiology using exome sequencing, also analyze variants of uncertain significance (VUS) in our patients and in other global 46,XY DSD cases. We will perform the analysis of gene copy number variations (CNVs). DSD diagnosis requires tertiary centers multidisciplinary team, unfortunately DSD information is not widespread among pediatricians and clinicians of primary and secondary care. The lack of information and experience by these clinicians creates a barrier in the approach, leading to a delay diagnosis and an inadequate management. For this reason the development of an application (APP) systematizing the approach of these patients will provided information for a better clinical care. In this study, 153 undetermined 46,XY DSD patients will be recruted to undergo whole exome sequencing. The data obtained will be analyzed on Franklin genoox platform, and the variants will be classified according to the American College of Medical Genetics and Genomics criteria. VUS will be analyzed and compared with other previously published VUS in 46,XY DSD, and evaluated on the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home) and LOVD3 database (https ://databases.lovd.nl). Application development will be carried out in compliance with local privacy and data security regulations. (AU)