PORTFOLIO

Congenital defects such as disorders of sexual differentiation are rare diseases that present considerable challenges for physicians, parents and affected individuals. These challenges include surgical correction, management and, in some cases, gender assignment that creates significant physical, emotional and psychological burdens on affected patients. Unfortunately a large fraction of human cases of disorders of sexual development are unexplained, despite substantial progress in our understanding of the molecular regulation of testicular and ovarian development. These observations clearly indicate that a significant number of genes (or regulatory regions of known genes) involved in sex determination remain to be identified.

The goal of this project is to develop new genetic tests for individuals or families with disorders of sexual development. For this purpose, we use cutting edge techniques in human and mouse genetics to investigate the complex mechanisms of gonadal differentiation. In particular, we will develop new genetic tools and apply them to a large cohort of unresolved cases of patients born with disorders of sexual development in order to reveal new genes and pathways involved in gonadal development. For this purpose, we will For unresolved cases of patients born with disorders of sexual development, we use array comparative genomic hybridization (aCGH) to detect micro-deletions or duplications as well as exome sequencing of the entire coding portion of the genome to screening for point mutations or small deletion/insertion events in >20,000 genes.

This project supported by the Gebert Rüf Stiftung is of high significance since it aims at identifying new genes and pathways involved in testis and ovarian development. For this purpose, we use cutting edge techniques in human and mouse genetics to investigate the complex mechanisms of gonadal differentiation. A major expected outcome is the development of new genetic tests to improve diagnosis and genetic counselling practices for individuals or families with disorders of sex development.

We discover the existence of a large genetic program (more than 800 genes) called core adreno-gonadal program (CAGP) initiated in developing gonads prior to sex determination. This program is required for optimal gonadal development and their capacity to differentiate either as a testis or an ovary. Second, our genetic analysis performed on a cohort of sex reversed patients identified already robust CNVs in three 46,XY DSD patients and in one 46,XX DSD patient, these variants being currently under the process of validation.

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