Uncovering the Role of Genetics in Neurodevelopmental Disorders

By Niki Akbarian

Neurodevelopmental disorders (NDDs) are heterogeneous conditions characterized by atypical development of the nervous system, which results in cognitive impairment and deficits in communication, behavior, and motor skills. 1 Intellectual disability, autism spectrum disorder (ASD), attentiondeficit/hyperactivity disorder (ADHD), neurodevelopmental motor disorders such as Tourette Syndrome, and specific learning disorders including reading disabilities are NDDs that affect 15-20% of children worldwide. 2 Comorbidity among NDDs is pronounced as they can co-occur with one another and/or with psychiatric disorders such as anxiety, depression, psychosis, and schizophrenia. 1 In addition, the clinical symptoms of NDDs overlap significantly, making their diagnosis and treatment challenging. Dr. Cathy Barr–a Senior Scientist at the Krembil Research Institute and the Neurosciences & Mental Health Program at the Hospital for Sick Children (SickKids)–investigates the genetics of NDDs and psychiatric disorders, which is one of the most effective approaches to understanding their underlying basis.

Dr. Barr completed her Ph.D. in molecular biology at the M.D. Anderson Cancer Center, University of Texas, and subsequently pursued her postdoctoral training at Yale University and SickKids. Although Dr. Barr started her postdoctoral training at SickKids with a specific focus on the genetics of Tourette Syndrome, she then broadened her field of study as she witnessed the extent of overlap between the genetics and clinical symptoms of Tourette Syndrome and other NDDs, such as ADHD and reading disabilities. Currently, Dr. Barr and her research team are attempting to identify genes involved in childhood NDDs, their function, and mechanisms that alter their function.

Over the past few decades, more than 1,500 genetic risk alleles associated with NDDs have been identified, 3 most of which alter the expression of genes by influencing their splicing or transcription. Interestingly, some of the identified genes are known to be shared among various NDDs. For example, Dr. Barr and her research team demonstrated that several genes associated with reading disability are also related to the autism spectrum disorder. While these genes undergo more severe changes in autism compared to reading disabilities, in both disorders, they are suspected to interfere with the neural development of brain regions implicated in language functioning. Specifically, an imbalance between excitatory and inhibitory neurons enriched with affected genes is suggested to underlie the clinical manifestation of these disorders.

Neural Migration

Another potential mechanism impacted by the genes involved in the pathology of reading disabilities and autism is neural migration. Neural migration is a critical process in the normal development of the nervous system that regulates the migration of cells into appropriate spatial positions relative to each other. 4 To understand how neural migration may differ in reading disabilities, Dr. Barr and her research team collected blood cells from children with reading disabilities and turned them into induced pluripotent stem cells and subsequently neural precursor cells. Thereafter, they examined how fast these neural cells could migrate in vitro. It was observed that neural cells from children with reading disabilities migrated faster and further than neural cells from their strong reader siblings. These deviations in neural migration can lead to the mislocalization of neural cells, resulting in improper development and functioning of brain circuits. 5 In her future research, Dr. Barr aims to complement these findings with neuroimaging data in order to compare the in vitro and in vivo behavior and migratory patterns of neural precursor cells. Further, it is of interest to understand how changes in the neural migration, in turn, impact the function and development of the brain in children with reading disabilities.

Moreover, recent international collaborations have made it possible to gain new insights into how specific variations in genes result in the pathology of NDDs. For instance, by using a Toronto-based sample, as well as the dataset from the GenLang consortium, an international network that facilitates large-scale genomic investigations, 6 Dr. Barr and her research team found that single nucleotide polymorphisms, defined as the substitution of a single DNA building block, in the Dedicator of

Dr. Cathy Barr

Senior Scientist at the Neurosciences &Mental Health Program, The Hospital forSick Children, Senior Scientist at the Krembil Research Institute, Professor in the Departments of Psychiatry and Physiology and the Institute of Medical Sciences, University of Toronto

Cytokinesis 7 (DOCK7) gene alter its splicing, yielding the production of an abnormal proportion of one DOCK7 protein variant over another. It is known that the DOCK7 protein is crucial for cortical neurogenesis and neural migration. 7 This explains how the substitution of a single nucleotide in the DOCK7 gene may impact neural migration and brain development in reading disabilities.

The Future Outlook

In addition, advances in genetic techniques also promise breakthroughs in the future. As Dr. Barr notes, “it took years of doing things that didn’t work out. We had no idea they weren’t going to work because the genetics are just so much more complex, and the tools that we used back then just wouldn’t work.” Genome engineering with CRISPR/Cas9, a novel method for genome editing that allows DNA break and permanent addition or deletion of genome sequences, 7 is an example of a newly developed method that can be a great asset to better understand the function of genetic risk alleles of NDDs and their mechanisms of action. Indeed, due to various complexities, the field of genetics is filled with tremendous obstacles for both trainees and principal investigators. However, as Dr. Barr states, “if you love it, you will figure it out.” The key in this field is to keep going and to learn from mistakes and challenges.

Despite all the valuable discoveries in the genetic studies of NDDs, it is still too early to translate this knowledge into clinical practice in order to change the therapeutic targets and the clinical care for these disorders. However, as Dr. Barr says, “just knowing that disorders like reading disabilities are familial, that they are inherited, that there is a neurobiological basis for them, that it’s not children’s fault, that they’re not dumb, and that 5% of other kids also have reading difficulties can be really helpful to families.” The truth is that there is a community of people, including geneticists and scientists, that would understand, support, and help children with NDDs to thrive in life.

References

1. Mullin AP, Gokhale A, Moreno-De-Luca A, et al. Neurodevelopmental disorders: Mechanisms and boundary definitions from genomes, interactomes and Proteomes. Translational Psychiatry. 2013;3(12).

2. Francés L, Quintero J, Fernández A, et al. Current state of knowledge on the prevalence of neurodevelopmental disorders in childhood according to the DSM-5: A systematic review in accordance with the Prisma Criteria. Child and Adolescent Psychiatry and Mental Health. 2022;16(1).

3. Leblond CS, Le T-L, Malesys S, et al. Operative list of genes associated with autism and neurodevelopmental disorders based on Database Review. Molecular and Cellular Neuroscience. 2021;113:103623.

4. Rahimi-Balaei M, Bergen H, Kong J, Marzban H. Neuronal migration during development of the cerebellum. Frontiers in Cellular Neuroscience. 2018;12.

5. Pan, Y. H., Wu, N., & Yuan, X. B. (2019). Toward a Better Understanding of Neuronal Migration Deficits in Autism Spectrum Disorders. Frontiers in cell and developmental biology, 7, 205. https://doi. org/10.3389/fcell.2019.00205

6. Genlang Consortium [Internet]. GenLang. [cited 2023Jan24]. Available from: https://www.genlang.org/

7. Watabe-Uchida M, John KA, Janas JA, et al. The RAC activator dock7 regulates neuronal polarity through local phosphorylation of Stathmin/OP18. Neuron. 2006;51(6):727–39.

8. Ran, F., Hsu, P., Wright, J. et al. Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8, 2281–2308 (2013). https://doi. org/10.1038/nprot.2013.143