Description

Malformations of cortical development (MCD) constitute a group of rare congenital, mainly genetic brain malformations leading to lifelong impact on health of affected individuals who may suffer froma range of developmental disabilities including cerebral palsy, epilepsy, intellectual disability, andautism. Although next-generation-sequencing (NGS) technologies have accelerated the discovery of novel candidate genes for MCD, they do come with a number of limitations. NGS produces largeamounts of data including variants of unknown clinical significance (VUS; referred to as class 3 variants, i.e. potentially but not proven disease-causing). In parallel with familial segregation studies and confirmation in a sufficiently large number of patients sharing the same phenotype, these unclassifiedvariants should ideally be validated by testing the functional effect on protein or biological process inanimal or cell system models.
This research proposal focuses on the study of variants of unknown clinical significance in MAN2C1 and CTDP1 identified in patients with MCD. Clinical data, DNA and skin fibroblasts of these patients are available and preliminary work on the function of the genes is ongoing. Impact on cell cycle, migration and apoptosis will be investigated in neuronal progenitor cells (NPC). To obtain these NPC, skin fibroblasts of the patients will be reprogrammed to induced pluripotent stem cells (iPSC) which inturn will be differentiated to NPC. The results in patient NPC will be compared with those of healthycontrol subjects and to NPC in which the candidate gene was deactivated by CRISPR / Cas9.
This research project will shed light on the role of MAN2C1 and CTDP1 in brain development. Inaddition, confirming their association with brain malformations allows identification of additionalpatients with changes in these genes in the future. Confirming a genetic diagnosis in a patient withMCD facilitates genetic counseling of the patient and the family, including the option to choose preimplantation genetic diagnostics to avoid recurrence in a subsequent pregnancy.
AcronymANI253
StatusNot started
Effective start/end date1/10/2030/09/22

    Flemish discipline codes

  • Developmental neuroscience

    Research areas

  • BRAIN DISORDER

ID: 52742318