Neurodevelopment and Neurodegeneration

Disorders of the human nervous system have been dichotomized classically between early onset neurodevelopmental traits and later onset degenerative phenotypes. However, as we understand the fundamental mechanisms of neurogenesis, renewal and homeostasis, these “classical” lines are blurring and an emergent picture suggests a more complicated causality model across neurological disorders. One of the areas of focus in the ACT-GeM is thus to understand how genetic variation can impact the development and homeostasis of the nervous system. As part of this work, we have developed animal and cellular models to study basic neurodevelopmental processes; to discover new genes and alleles that contribute to neurodevelopmental and neurodegenerative disorders in humans; and to enable the development of rational therapeutic paradigms.

Through local, national, and international collaborations that intersect the basic sciences with the clinical enterprise, we recruit and study the genetic architecture and pathomechanisms of patients with a variety of neurological disorders. Some examples include:


Autism is a multifactorial neurodevelopmental disorder characterized by deficits in communication and social interaction, and repetitive behaviors. The prevalence for this condition is ~1% worldwide with a 4:1 male to female ratio. Several co-morbidities have been associated with Autism Spectrum Disorders (ASD) including intellectual disability, craniofacial malformations, gastrointestinal problems, and heart malformations. Our researchers are currently investigating the candidacy of select genetic determinants and specific pathways in the development of the disorder [Beunders et al, 2013, Bernier et al, 2014, Sugathan et al, 2014, Turner et al, 2015, Guissart et al, 2018]. We are also identifying major chromosomal lesions (deletions and duplications) for both neuroanatomical phenotypes and associated comorbidities [Golzio et al, 2012, Carvalho et al, 2014, Dauber et al, 2013, Bernier et al, 2014]. Ultimately, we hope to contribute to the rational stratification of this highly heterogeneous group of disorders; to define common pathways that might predict manageable co-morbidities; and to help design rational therapeutic paradigms for some AS/ASD patients.

Neuromuscular Disorders

Within the muscular dystrophy clinical spectrum lie several disorders that in principle weaken the musculoskeletal system and hamper locomotion. The combined prevalence of these often devastating disorders is 0.025% (19.9 to 25.1 affected individuals every 100,000 live births). Our researchers have investigated a range of muscular dystrophies such as centronuclear myopathies [Nesin et al, 2014], Charcot-Marie Tooth [Gonzaga-Jauregui et al, 2015], essential tremor [Schulte et al, 2014], adult onset limb girdle muscular dystrophy [Sarparanta et al, 2012] and primary dystonia [Zech et al, 2015], shedding light into the causality of identified genes and variants; elucidating affected pathways; and measuring genetic burden in biological modules. Our broad spectrum of methodologies allowed us to identify an isolated case of phenotypic expansion for a known muscular dystrophy gene, SMCHD1, that implicated the locus with isolated arhinia and Bosma arrhinia microphthalmia syndrome [Shaw et al, 2017]. This example highlights the power of our in vivo and in vitro tools to explain pleiotropy. The progressive nature and juvenile/adult onset of these disorders render them attractive candidates for new therapeutic designs, which we hope to pursue.

Schizophrenia (SZ)

With a prevalence of ~1% worldwide, schizophrenia is a neurological condition that is characterized broadly by reduced motivation and social engagement, and a higher incidence of hallucinations. Both genetic and environmental factors contribute to the etiology of the disorder. Using mouse and zebrafish animal models and cell-based assays, our researchers are establishing how specific genetic lesions can lead to neuroanatomical and behavioral alterations that may be relevant to the disorder [Kamiya et al, 2008, Zoubovsky et al, 2015, Fromer et al, 2016, Loviglio et al, 2017, Gusev et al, 2018]. Through these studies, we hope to understand the genetic architecture of SZ; to predict (and enable the management of) systemic co-morbidities; and to identify subsets of SZ patients who might benefit from innovative drug discovery paradigms.

Structural Neuroanatomical Defects In Neonates And Young Children

Rare disorders that result in central and/or peripheral nervous system abnormalities are usually seen in less than 0.1% of the general healthy population. Our researchers have investigated a wide spectrum of such disorders that though rare, potentially inform a plethora of other conditions with similar clinical presentations [Niceta et al, 2015, Borck et al, 2015, Wortmann et al, 2015, Magini et al, 2014, Brooks et al, 2014, Frosk et al, 2017, Ta-Shma et al, 2017, Anttonen et al, 2017, Küry et al, 2017, Reijnders et al, 2017, Stankiewicz et al, 2017, Reijnders et al, 2017, Guissart et al, 2018, Del Dotto et al, 2019, Frints et al, 2018, Khan et al, 2019, Khan et al, 2019, Niihori et al, 2019, Ansar et al, 2019]. Additionally, we have found that the study of rare disorders can broaden our knowledge of unanticipated biological phenomena, complex inheritance mechanisms, as well as inform the genetic and cellular mechanisms that underscore the persistently mysterious phenomena of variable expressivity and non-penetrance [Margolin et al, 2013, Muto et al, 2018, Guissart et al, 2018, Reijnders et al, 2017]. Together, we anticipate that such studies will promote the concept of Personalized Medicine and will help improve not only the diagnostic, but also the prognostic value of the Human Genome.