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Application of whole exome sequencing to identify pathogenic variants in 46,XY partial gonadal dysgenesis

Grant number: 15/04763-4
Support type:Regular Research Grants
Duration: May 01, 2016 - April 30, 2018
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Andrea Trevas Maciel Guerra
Grantee:Andrea Trevas Maciel Guerra
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers: Ana Paula dos Santos ; Fábio Rossi Torres ; Gil Guerra Júnior ; Maricilda Palandi de Mello


46,XY partial gonadal dysgenesis (XY PGD) is a rare and often sporadic disorder. It is characterized by genital ambiguity with partial testicular differentiation and a 46,XY karyotype. Mutations have been described in the NR5A1 gene and in other genes which participate in gonadal differentiation, as SRY, WT1, SOX9 and LHX9, but in most cases the etiology remains unknown. Currently, next-generation sequencing technologies enable the search for pathogenic variants across the human genome. The sequencing of the complete exome (whole exome sequencing, WES) enables the detection of pathogenic mutations in the complete coding region of an individual and has been applied to the study of conditions whose etiology is currently unknown such as XY PGD. This project aims to look for new pathogenic variants in patients with XY PGD in order to identify the presence of pathogenic mutations that may be the cause of this condition and possibly identify new genes involved in testicular differentiation. Our sample will comprise four to five "trios" (patients and their parents). DNA samples will be fragmented to allow the construction of a DNA library. The fragments will be flanked with adaptors, and solid phase PCR will be performed to generate clusters of DNA molecules. Sequencing will be performed on the Illumina platform using nucleotide reversible terminators and fluorophores. Sequence analysis by bioinformatics will be carried out to identify pathogenic mutations, either heterozygous ("de novo" or inherited from the mother) or homozygous (recessive inheritance). The presence of these variants will be validated by Sanger sequencing and subsequently investigated in a control group of at least 100 individuals. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FABBRI-SCALLET, HELENA; DE SOUSA, LIZANDRA MAIA; MACIEL-GUERRA, ANDREA TREVAS; GUERRA-JUNIOR, GIL; DE MELLO, MARICILDA PALANDI. Mutation update for the NR5A1 gene involved in DSD and infertility. Human mutation, v. 41, n. 1, p. 58-68, . (15/04763-4, 18/19445-6, 13/05603-5)

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