Disorders of Sex Development: molecular evaluation of syndromic cases searching for new genes

• Grant number: 24/15917-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Gil Guerra Júnior
• Grantee: João Lucas Gonçalves Sena Afiune
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Disorders of Sex Development (DSD) can manifest with genital ambiguity, pubertal delay, atypical puberty or infertility. Late or erroneous diagnosis of a patient with genital ambiguity can lead to a sex definition that is not always correct. Therefore, when faced with a patient with DSD, especially children with genital ambiguity, the main objective is the accurate diagnosis of its etiology. Advances in the area of molecular biology in recent years have allowed us to identify the etiology of a greater number of cases, previously classified as unclear or idiopathic. Approximately 20 to 25% of cases of DSD with genital ambiguity are associated with other malformations, and are defined as syndromic. Molecular evaluation by next-generation sequencing, especially of syndromic DSD cases, may allow the discovery of new genes that participate in the process of sexual differentiation. The Interdisciplinary Group for the Study of Sex Determination and Differentiation (GIEDDS) of the State University of Campinas (UNICAMP) is responsible for treating DSD cases in the Campinas region (SP) and is a national reference. From January 1989 to December 2023, GIEDDS - UNICAMP treated approximately 2,000 DSD cases. In recent years, GIEDDS - UNICAMP has been able to evaluate some of these unclear cases by exome or genome. This is still a field little explored in the literature. Therefore, the main objective of this study will be to verify the exome or genome results of patients with genital ambiguity, with an associated syndromic condition and without a defined etiological diagnosis treated at GIEDDS - UNICAMP. In addition, we aimed to verify whether the observed molecular alterations may be related to sexual differentiation pathways, and also to verify the frequency of entries in OMIM of terms related to DSD and genital ambiguity. Syndromic DSD cases were considered to be those with a 46,XX or 46,XY karyotype without structural alteration of the autosome or sex chromosome and without mosaicism and that, in addition to genital ambiguity, presented another major malformation (central nervous system, heart, urinary tract, skeleton, or others), and/or accompanied by pre- and/or postnatal growth disorder and/or neurodevelopmental disorder, and/or at least three minor dysmorphisms. The data will be obtained from the analysis of the HC - UNICAMP medical records: year of birth, year of first consultation, age at first consultation, sex of rearing, severity of genital ambiguity, associated syndromic condition, karyotype, molecular study performed (date, type, and result). For research in OMIM, the following entry terms will be used (alone or in combination): "small penis" or "micropahllus"; "clitoral enlargement" or "clitoral hypertrophy"; "small testes" or "small testicles" or "microrchidia"; "cryptorchidism"; and "hypospadias".