Investigation of Oligogenic Inheritance in Patients with 46,XY Disorders of Gonadal Differentiation Through Genomic Analysis

• Grant number: 24/05003-2
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2024
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Gil Guerra Júnior
• Grantee: Gil Guerra Júnior
• Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Helena Fabbri Scallet ; Mara Sanches Guaragna
• Associated scholarship(s): 24/18139-0 - INVESTIGATION OF OLIGOGENIC INHERITANCE IN PATIENTS WITH 46,XY DISORDERS OF GONADAL DIFFERENTIATION THROUGH GENOMIC ANALYSIS, BP.TT

Abstract

Disorders of Sex Development (DSD) encompass a group of congenital conditions characterized by incomplete or disordered genital and/or gonadal development leading to a discordance between genetic, gonadal, and phenotypic sex. Considering that the same genetic variant has become associated with a broad phenotypic spectrum among unrelated individuals with DSD, the possibility of the involvement of two or more genes has been suggested. This could result in their combined effects leading to a worsening of the phenotype, describing some cases of DSD. This study initially proposes to carry out a molecular investigation of 20 46,XY DSD patients through exome sequencing (WES). We aim to identify variants in genes involved in sexual development, as well as, in candidate genes whose association with DSD has not been established. Once identified, digenic or oligogenic inheritance will be investigated using bioinformatics tools, such ORVAL/VarCoPP and Cytoscape. These tools are used to establish an interaction network between the identified genes. The variants will be validated by Sanger sequencing and, its impact on protein function will be assessed through in vitro analysis. Those will involve reporter gene assays and Western Blot. We believe that this study could contribute to a better understanding of the interaction pathways between genes involved in sexual development and candidate genes, providing an explanation for the range phenotypic variability in DSD cases. (AU)