Center for Medical Genetics Center for Medical Genetics

Development genetics

  • Research focus

CIS-Code: disruption of the regulatory code in human genetic disease


In the personal genome era, an increasing number of variations outside the coding portion of the genome is found. Their biological function is often unclear. Human genetic disorders are classically caused by mutations in genes, representing the coding portion of the genome. However, many other mechanisms can impair normal gene function, and potentially lead to disease. Some genes, especially those that play a role in development, need a strict expression in time, place and quantity. The instructions for correct expression can be found in the so-called regulatory code of the genome, which is yet far from deciphered. Studies of specific human genetic disorders have been very useful to uncover disease-causing disruptions of the regulatory code, also called “cis- ruptions”.


Our general aim is to identify novel cis-ruptions in several developmental disorders - such as BPES (FOXL2 region), anterior segment dysgenesis (PAX6, FOXC1, PITX2, PITX3 regions), SHOX-related disorders - for which unique patient collections are available. Newly identified cis-ruptions, such as genetic changes in highly conserved non-coding elements, will be validated using in vitro assays (reporter assays; chromosome conformation study) and in vivo assays (zebrafish, mouse). An extensive validation of these genetic defects is of utmost importance before interpreting them in a clinical context. Finally, this CIS-CODE project will contribute to cracking the regulatory code in our genome, and new cis-ruption mechanisms may serve as a model for other genetic, acquired and complex disorders.

Next-generation genomics for identification of new disease genes and mechanisms in 46,XX and 46,XY disorders of sex development


Disorders of sex development (DSDs) represent an array of congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. Recently, DSD experts proposed a classification based on the karyotype and where possible on the underlying genetic defect, in order to facilitate basic and clinical research and patient care. However, current knowledge allows a molecular diagnosis in only roughly 20% of patients. Mutagenesis studies in mice and genome-wide approaches in humans accelerate the discovery of genes involved in gonadal development and DSD. New mechanisms such as regulatory mutations and multiple mutations are emerging causes of DSDs. These advances are refining the diagnosis and pave the way to improve management in affected children. Indeed, patients and professionals face challenging decisions regarding gender assignment, genital surgery and lifelong care. In addition, identification of the molecular causes of DSDs provides insight into the biology of gonadal development.


Our general aim is to identify new disease genes and mechanisms in 46,XX and 46,XY DSD patients using the next generation of genome-wide technologies.

Last updated: 08 December 2015 - 15:44
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