Functional genomics and sex development


The development and function of the reproductive system are critically important for the physical and emotional wellbeing of an individual. They are also necessary for reproduction, and the continuation of the species.

Disorders of sex development (DSD) – also known as intersex – are conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD are one of the most common congenital disorders, occurring in up to 1% of newborn babies. Some DSD are diagnosed later in life, affecting around 5-7% of the population. These conditions represent a major paediatric concern and a significant healthcare burden due to difficult clinical management and their common association with gonadal cancer and infertility.

Clinical presentations of DSD are very heterogeneous, including:

  • Complete XX or XY sex reversal (genetic sex not corresponding to the anatomical sex)
  • Gonadal dysgenesis (atypical development of the gonad)
  • Primary ovarian insufficiency (menopause before age 40)
  • Reproductive tract anomalies

One of the major challenges in the diagnosis and management of these conditions is the poor understanding of their causes, both genetic and environmental. This current gap in knowledge is mainly due the lack of translational studies to define the function of the complex network of genes that regulate the formation and differentiation of the gonads and the reproductive tract.

The Functional Genomics and Sex Development group utilizes genome-wide analyses, molecular biology approaches, and gene editing strategies – including CRISPR – to model human conditions.

The goal of our team is to: 1) identify the causes of DSD; 2) define the role of the genes involved in the formation and differentiation of the reproductive system, and 3) understand how genetic makeup and environment interact during sex development.

MRKH Syndrome and Müllerian Anomalies

The Müllerian ducts are embryonic structures that develop into the female reproductive tract, which comprises oviducts, uterus, cervix, and upper part of the vagina. Atypical development of the Müllerian ducts result in Müllerian anomalies, including – among others – uterus bicornuate, unicornuate, and didelphys. The most severe of which is known as Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome, which is characterized by the incomplete development of uterus and/or vagina. The aetiology of MRKH Syndrome and other Müllerian Anomalies is currently unknown.

Sex determination and development

When the gonads first appear during early embryogenesis, they are undifferentiated (also called bipotential gonads). Depending on the chromosomal sex (XX in females, and XY in males), a specific developmental program is activated leading to the differentiation of ovaries or testes. Disorders of sex development (DSD) – or intersex conditions – occur when such a complex program is not executed properly. The genetic and cellular events regulating gonadal development are still poorly understood, and currently 10% of 46,XX DSD (XX males) and 70% of 46,XY DSD (XY females) are unexplained. 

Premature menopause

Menopause occurs physiologically around 51 years of age. The ultimate determinant of menopause is the age-related decrease in number of ovarian primordial follicles, which contain the eggs and are also known as the ovarian reserve. Premature menopause ensues when the ovarian reserve is depleted earlier than expected. When menopause occurs before age 40, it is called primary ovarian insufficiency (POI), affecting 1% of the general female population. When menopause occurs between age 40 and 50, it is called premature ovarian aging (POA), which affects around 4-7% of women. To date, the cause of POI remains unknown in 90% of cases.

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