Cardiogenetica

Background

Disorders of brain functioning are heterogeneous, but result in common effects with detrimental consequences in daily life. Disorders of brain functioning can be either developmental or occur later in life, i.e. after a brain hemorrhage or trauma. The main focus of our group is to unravel the genetic causes of developmental brain disorders and more specifically those causing cerebral palsy (CP). CP is the leading cause of motor impairment in children due to damage in the developing brain. It is often accompanied by a wide range of medical conditions such as intellectual disability, learning difficulties, speech and language deficits, epilepsy, autism spectrum disorder and visual and/or hearing impairment. Perinatal oxygen deprivation was long thought to be the leading cause of CP, but recent studies demonstrate this as a cause in at most 12% of patients and genetic causes of CP are increasingly being discovered. However, insights into underlying mechanisms leading to CP are still limited.

A subgroup of disorders that lead to CP are cerebrovascular disorders, e.g. COL4A1- and COL4A2-related disorders. In these disorders, a weakening of the cerebral blood vessels leads to an increased risk of cerebral hemorrhage; this can occur already during pregnancy or in early childhood, but in other patients, the disorder presents only at a later age, e.g. with intracranial aneurysm (widening of the blood vessels of the brain). The underlying mechanism of cerebrovascular disease associated with COL4A1- and COL4A2-variants in both CP and adult-onset intracranial aneurysms is still not fully understood. In addition, studies focused on the identification of additional genetic factors in both infantile and adult cerebrovascular disorders, including intracranial aneurysms, may contribute to unravel underlying pathomechanisms.

Malformations of cortical development (MCD) constitute of a group of rare congenital brain malformations that can also present as CP and associated features. Disorders in the MCD spectrum include lissencephaly (smooth brain), heterotopia (aberrantly located bands or clusters of neurons), and polymicrogyria (multiple small convolutions of the cerebral cortex) with or without microcephaly (small brain) or megalencephaly (large brain). Despite a significant effort in the identification of genetic causes underlying MCD, 60% of MCD cases currently remain molecularly unexplained. Alternative molecular diagnostic approaches are needed to increase the genetic uptake in MCD patients. Additionally, for this subtype of brain disorders, a better understanding of mechanisms involved will be crucial to make steps forward in improvement of care and treatment.

Goal

Our research focuses on deciphering the genetic background and underlying pathomechanisms of these subgroups of brain disorders. We strongly believe that our research contributes to diagnosis and improvement of patient care and can be the entry point for the development of novel targeted therapies.

Strategy

We use state-of-the-art approaches including exome and genome sequencing and transcriptomics to gain insight into the molecular background and pathomechanisms of these groups of disorders. In vivo modelling of COL4A1- and COL4A2-related disorders is also part of our portfolio.

Disorders under investigation

COL4A1- and COL4A2-related disorders, cerebral aneurysm, cerebral palsy, KIF1A-related NESCAV syndrome, malformations of cortical development, mTORopathies, tubulinopathies

Team members

Marije Meuwissen, Dorien Schepers, Ilse Luyckx, Bart Loeys, Katrien Janssens, Anna Jansen, Diane Beysen, Berten Ceulemans, Merlijn Nemegeer, Liene Thys, Jessica Rosenblum, Charlotte Claes