Identification of new disease-associated genes in GnRH deficiency using Whole Exome Sequencing

The Hypothalamic-Pituitary-Gonadal (HPG) axis is widely considered as the driving force of reproduction in all vertebrates, including human. Gonadal Releasing Hormone (GnRH) secreted by the GnRH neurons from the hypothalamus is the central regulator of this axis. GnRH secretion during puberty onset and adulthood stimulates the production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland, that in turn regulate germ cells maturation and sex hormone production in the gonads. GnRH neurons originate outside the central nervous system (CNS) in the olfactory placode during embryonic development. Once fate-specified, they migrate along the olfactory axons throughout the olfactory bulb, to reach the preoptic area of hypothalamus. Kallmann Syndrome (KS) is a rare disorder (1:10’000 cases in males, 1:50’000 in females) characterized by GnRH deficiency, resulting in absence of puberty, infertility and combined by anosmia (lack of sense of smell). Mutations in more than 15 genes have been found in KS patients throughout last 20 years; however, the genetic causes of ~70% of the cases are still unknown. Kallmann Syndrome is characterized by phenotypic variability and oligogenic architecture. The goal of this thesis is to use next generation sequencing technologies as Whole Exome Sequencing to identify new genetic networks underlying this disorder.