Developmental Brain Disorders Laboratory
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Developmental brain disorders (DBD) encompass a highly heterogeneous group of diseases characterized by impairments in cognition, communication, behavior or motor functioning as a result of atypical brain development. This group of disease includes intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder, specific learning disorder, and motor disorders. Neurodevelopmental disorders, also extends to conditions such as schizophrenia and epilepsy. Epidemiological studies show that co-occurrence of several neurological features is the rule. For example, up to 70% of individuals with ASD present with ID. Similarly, the prevalence of epilepsy in people with ID is 26%. Cerebellum developmental defects are recognized to be responsible of specific neuropsychological deficits and pediatric onset-ataxia presents often as developmental delay and intellectual disability. This phenotypic overlap is also mirrored at the genetic level. As an example, CNVs or genes (i.e. the 16p11.2 deletion, SHANK3, SCN2A) linked to ASD are also found in ID, epilepsy or schizophrenia. Taken together, these observations support the existence of common pathophysiological mechanisms for DBD which should be viewed as a continuum of developmental brain dysfunction.
Despites recent progresses, a large number of cases remain unexplained. With a combined prevalence of up to 3% of the population, DBD accounts for 10% of the total health care cost in most Western countries. Understanding the biological bases of these conditions is thus a major medical and socio-economical challenge.
Over the last decade and using state-of-the-art genetic and genomics technologies, our group has characterized numerous chromosomal anomalies and disease-causing mutations responsible for DBD. To evaluate the functional impact of newly identified genomic variants, we use several complementary approaches based on models such as induced human neural stem cells, mice and zebrafish.
Projects and achievements 2018-2020:
Our research projects and objectives over the last years can be summarized as below:
Decipher the genetic architecture of DBD
Our new objectives include the use of genome sequencing and alternative methods (e.g. optical mapping) to characterize structural variants involved in DBD.
- Identification of bi-allelic mutations in DEGS1 as a new cause for hypomyelinating leukodystrophy with potential treatment (doi: 10.1172/JCI123959).
- Identification of mutations in Neurofascin (NFASC) in patients with intellectual disability, motor impairment and peripheral neuropathy (doi: 10.1093/brain/awz248.).
- Interaction of CNVs with incomplete penetrance and recessive mutations (doi: 10.1038/s41431-018-0124-4).
Identify the molecular causes of developmental cerebellar disorders with cognitive defects
Cerebellar defects are well known to cause imbalance and poor coordination. However, over the last decade, clinical and neuropsychological investigations highlighted the important role of the cerebellum in the acquisition of higher-order cognitive and affective skills. A better understanding of human cerebellum development should help to understand its role in cognition. We currently use exome sequencing in patients from Necker hospital or from the Middle East to identify new genes involved in these disorders and we study the effect of the identified variants using cell, fish or mouse models.
To better understand how early hindbrain developmental defect could be involved in DBD, we will characterize the disruption of the transcriptional program caused by mutations in early expressed hindbrain transcriptional factors. Finally, we will better characterize the cohort of patients with early-onset cerebellar atrophy, (including CACNA1G mutation), a group of patients for whom treatment .
- Demonstration that gain of function mutations in the CACNA1G calcium channel gene cause a new encephalopathy with therapeutic perspectives (doi: 10.1093/brain/awy145).
- To better understand how early hindbrain developmental defect could be involved in DBD, we will characterize the disruption of the transcriptional program caused by mutations in early expressed hindbrain transcriptional factors.
Physio-pathological mechanisms involved in the neurological symptoms caused by a defect in protein N-glycosylation
The disruption of protein N-glycosylation is responsible of a group of genetic diseases frequently associated with ID and cerebellar atrophy/hypoplasia. The reason why the central nervous system and mostly the cerebellum are especially sensitive to this defect is totally unknown. This project aim is to identify the cellular and biochemical targets involved in these diseases using a conditional knockout mouse model for the Srd5a3 gene.
- Identification of a mechanism that explain the sensitivity of the cerebellum development to N-glycosylation defect using a mouse model for a congenital disorder of glycosylation (doi: 10.7554/eLife.38309).
- Assessment of the Trisomy 21 screening using cell-free circulating DNA sequencing in pregnant women.
- Characterization of the clinical spectrum of patients with ASD and defined genetic etiology
Research: a scientific adventure
Our goal: to better understand genetic diseases to better treat them.