Malformations of cortical development

 The development of the cerebral cortex is extremely complex but can nevertheless be divided into different, partly overlapping stages. Interference with one or more of these processes by genetic or external factors may result in malformations of cortical development (MCD). The most prevalent MCDs include lissencephaly/subcortical band heterotopia, polymicrogyria, periventricular heterotopia and focal cortical dysplasia. MCDs are an important cause of mental and motor impairment, severe epilepsy, intellectual disability, and autism. Patients require a lifelong multidisciplinary follow-up and treatment is restricted to symptom relief. Most MCD have a genetic etiology but there is extensive heterogeneity both with respect to genotypes and phenotypes. For the large majority of patients with MCDs, the exact etiology of their disorder is still unknown, leaving a considerable number of families not having access to counseling or prenatal diagnosis in order to prevent recurrence.

The different projects aim at the further identification of genes involved in the regulation of neuronal migration and the study of the functional consequences of mutations in these genes , starting from a patient-driven approach. This will result in mapping of major pathways involved in cortical development and function.

The general aims of the studies are:

• To search for new genes involved in malformations of cortical development
• To expand the genotype/phenotype knowledge of known genes/diseases involved in malformations of cortical development
• To develop in vitro tools to study functional consequences of genetic alterations
• To study changes in iPSC derived cortical neurons comparing patients and controls

Genetics of male infertility

Infertility is a problem affecting 10-15% of couples with a child wish. For about half of these couples, a male factor is (co-)responsible . Although for a lot of patients the origin of the problems can be detected, still approximately 30% remains undiagnosed. Two main categories of disorders can be distinguished: acquired and congenital. The last category can either be of genetic origin or can be due to a developmental disorder.

Our team is especially interested in men with a (presumed) genetic cause of male infertility and families with multiple affected cases. For infertile men for whom sperm cells can be retrieved either from the ejaculate or by testicular sperm extraction, in vitro fertilization, possibly with intracytoplasmic sperm injection (ICSI) might be a solution for their fertility problems. As a consequence, also potential genetic causes of infertility can be transmitted. Therefore, it is important to identify and study these genetic causes in order to be able to adequately counsel the couples.

The general aims of the studies are:

• To detect changes in the genome that are related to male infertility.
• To get more insight into the underlying mechanism and consequences of (known) causes of male infertility with a special focus on Y-chromosomal genes.
• To study genes expressed in testicular tissues, and therefore potentially involved in spermatogenesis.