Prof. Stephen Scherer

Prof. Stephen Scherer

Director of the University of Toronto McLaughlin Centre & the Centre for Applied Genomics at SickKids in Toronto

Dr. Scherer holds the GlaxoSmithKline-Canadian Institutes of Health Research Endowed Chair in Genome Sciences at The Hospital for Sick Children (SickKids) and University of Toronto (UofT) in Canada. He is the Director of the UofT McLaughlin Centre, as well as The Centre for Applied Genomics at SickKids. Dr. Scherer and his group contributed to the landmark discovery of gene copy number variation (CNV) as a common form of variation in DNA. They showed, contrary to classical genetics, that genes don’t always come in pairs of two along chromosomes. His team then identified CNV of specific neurodevelopmental genes to contribute to the etiology of autism, revealing this behavioral disorder can have a specific biological basis. The Database of Genomic Variants he founded facilitates thousands of CNV-based clinical diagnoses of autism, and many other diseases, each year, worldwide. His research is documented in over 500 peer-reviewed publications and he is one of the most highly cited scientists in the world. Dr. Scherer has won numerous honors such as a Howard Hughes Medical Institute Scholarship, and the Premier’s Summit Award for Medical Research. He is a distinguished Fellow of the Canadian Institute for Advanced Research, the American Association for the Advancement of Science, and the Royal Society of Canada. In 2014, he was selected as a Thomson Reuters Citation Laureate in the field of Physiology or Medicine for “the discovery of large-scale CNV and its association with specific diseases”.



Short Description of the Lectures:

1. Genome – Genes – Outcome

Autism Spectrum Disorder (ASD) is heterogeneous, both phenotypically and in its genetic architecture. There are now hundreds of genes found associated with ASD, with risk contributed by multiple types of rare and common genome-wide variation. Some individuals carry single rare (de novo or inherited) penetrant gene alterations. Others have multiple variants, and for these and others with ASD, a whole host of (poly)-genic risk factors may be involved.

Whole genome sequencing (WGS) technology has been launched worldwide by large-scale projects to study thousands of families from ASD cohorts and biobanks. The goal of this research is to decode entire genome sequences including all their genetic variants, link to available phenotype data, and make these massive genomic/phenotypic datasets available for scientific study. Before this, to find the complete spectrum of variants has required the incremental technologies of karyotyping, microarray, panel-sequencing and exome-sequencing. With WGS, an experiment costing about USA$1000 can complete the task in a single comprehensive step.  WGS sequencing has identified new variants in protein-coding and non-coding (e.g., lncRNA, regulatory) regions, in or near genes missed by other technologies.

A more complete view of the entire genome can increase the yield of findings relevant for ASD or its co-morbidities and provide context for their interpretation. Smaller CNVs and more complex SVs, often missed by other technologies, also contribute significantly in the aetiology of ASD. Approximately 100 gene and CNV regions currently have value for testing in ASD diagnostics. Through data consistent across many studies, genes involved in synaptic and neural adhesion, neural transcriptional regulation, and RNA processing are found to be involved in ASD, offering new entry points for drug development.

The presentation will provide an overview of results of the major published genetic and genomic studies, the data and resources available, and the most relevant scientific advances benefiting individuals and families with autism worldwide.

2. Advances in Genetic Testing for Autism Spectrum Disorder

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders affecting social communication, language, and behavior, and there can also be many medical complications involved. The underlying cause(s) in a given individual is often elusive, with the exception of clinically recognizable genetic syndromes with readily available molecular diagnosis, such as fragile X syndrome. Clinical geneticists approach patients with ASDs by ruling out known genetic and genomic syndromes, leaving more than 80% of families without a definitive diagnosis and an uncertain risk of recurrence. Advances in microarray technology, exome sequencing, and now whole genome sequencing are revealing rare genetic variants in genes with important roles in synapse formation, function, and maintenance. Many of these same genes now deemed etiologically relevant/diagnostic in ASD are found to be involved in intellectual disability, epilepsy, in neuropsychiatric disorders like schizophrenia and ADHD, and even in other complex conditions like cerebral palsy. Common genetic variants can also be involved as is being revealed through more recent polygenic risk score analyses. Somatic variants are now also known to be involved in ASD, further complicating interpretations. Notwithstanding these complexities, there is progress in genotype and phenotype correlations enabling the identification of penetrant genes and CNVs, and these can be used for confirmatory diagnosis, and to inform early diagnosis. This presentation will focus on the clinical genetics approach to ASDs, given the current state of knowledge about their complex genetic architecture.

3. Reflection Session