Researcher

Title

• Full Professor, Department of Pediatrics, Faculty of Medicine, University of Montréal
• Medical Geneticist, CHU Sainte Justine

• 2002-2004: Master's with thesis, Molecular Genetics of Developmental Disorders and Oncology, Genetics, Université René Descartes (Paris V). Supervisor: Munnich, Arnold.
• 1996-2003: Postdoctoral Fellowship, Specialization in Medical Genetics, Genetics, Université de Nantes. Supervisor: Moisan, Jean Paul.
• 1999- 2000: Equivalent to Doctorate, Doctor of Medicine, MD, Medicine, Université de Nantes. Supervisor: Moisan, Jean Paul.
• 1997-1998: Diploma, Neuromuscular Disorders, Neuromuscular Disorders, Université de Paris VI (Pierre and Marie Curie). Supervisor: Fardeau, Michel.

I am an associate professor at the University of Montreal in the department of pediatrics and neuroscience and work as a clinical researcher at the pediatric Hospital of Sainte Justine. I trained as a medical geneticist in France and subsequently completed a fellowship at the UC-Davis MIND Institute.

My research tackles the widening gap between the tidal wave of gene discovery and our poor understanding of rare genomic variants' effects on neurodevelopmental and psychiatric traits and risk for psychiatric disorders.

My lab combines genomic data from genotyping and whole-genome sequencing, transcriptomic information, neuroimaging data, cognitive and behavioral traits.

I have an extensive track record in investigating deletions and duplications at the 16p11.2 genomic loci. I

established the 16p11.2 European consortium to develop cohorts of individuals who carried these copy number variants. This showed that gene dosage at the 16p11.2 locus modulates cognition, behavior, brain structure, and connectivity.

We have now extended these investigations to ultra-rare non-recurrent CNVs and SNVs genome-wide. We use functional annotations of genes at the microscale (e.g., gene expression in cell types) and macro-scale levels (e.g., spatial patterns of gene expression in the brain) to understand the effect of genomic variants on cognitive, behavioral, and neuroimaging traits. This framework enables the investigation of undocumented genomic

variants too rare to be studied individually. We have aggregated and processed one of the largest datasets to investigate the effects of rare variants on dimensional measures of cognition and behavior and provide insights on mechanisms underlying risk for psychiatric conditions. This research is conducted within the genome to mental health network that I co-chair with Dr. Gur.

I have also worked since 2009 on large drug development programs and clinical trials in fragile X syndrome, a genetic condition associated with autism and intellectual disability. I conducted phase 1 and phase 2 trials testing the efficacy of treatments targeting specific mechanisms in Fragile X syndrome, a monogenic form of intellectual disability and autism.

• Copy number variants (CNVs)

Our studies of the 16p11.2 locus have shown that genomic dosage (deletions and duplications) modulate body mass index contribute and contribute to idiopathic obesity. We also showed that gene dosage at the same genomic locus modulates cognitive and behavioural traits as well as brain architecture.

However, recurrent CNVs such as 16p11.2 deletions and duplications represent a small fraction of the pathogenic CNVs identified in patients referred to the clinic for neurodevelopmental disorders. The vast majority of CNVs with clinical significance are too rare to be studied individually using association studies. Their effect sizes on cognitive traits measured as a continuum remain mostly undocumented. Methods developed in our laboratory have shown that the effect on cognition of rare CNVs can be accurately estimated by statistical models trained in the general population and psychiatric cohorts. We have developed web-based tools to predict effects of structural genomic variants on cognitions and autism risk.

• Neuroimaging genetic risk factors for autism and schizophrenia

Pathogenic copy number variants (CNVs) are associated with neuro-developmental psychiatric disorders such as autism spectrum disorder and schizophrenia. However, brain mechanisms mediating these genetic risks remain largely unknown. Our group has conducted structural MRI and resting-state functional connectivity neuroimaging studies of pathogenic CNVs. We showed that deletions and duplications of the same genomic interval modulate brain networks in opposing ways.

We have also shown that all pathogenic CNVs studied to date have moderate to large effect sizes on global and regional brain morphometry as well as functional connectivity. Effect sizes on MRI-derived measures are in line with symptom severity reported for these variants.

However, the guiding principles and mechanisms underlying relationships between CNV-related variations in brain architecture and the function of genes encompassed in these CNVs are unknown. Our lab is now focused on this question.

• Clinical trials in Fragile X syndrome

FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder. My group and other have conducted phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

• Fragile X-associated tremor/ataxia syndrome

We identified a new neurodegenerative disorder (Fragile X-associated Tremor Ataxia Syndrome, FXTAS) affecting carriers of premutation alleles in the FMR1 gene. This work improved care for previously misdiagnosed

patients.

Career Summary

Dr. Sébastien Jacquemont's research focuses on neuropsychiatric disorders of genetic origin. His team combines genetics, neuroimaging, biomarkers, and clinical approaches to understand how genetic mutations lead to neuropsychiatric symptoms and disability in patients.

The team has a strong interest in disorders associated with mutations in the FMR1 gene. In collaboration with other research groups, they identified a neurodegenerative disease associated with the FMR1 gene premutation (postural tremor and ataxia associated with fragile X premutation). This triplet-repeat disorder affects adult carriers of the premutation, who may develop ataxia, intentional tremor, cognitive decline, neuropathy, and parkinsonism.

In collaboration with industry and some academic groups, Dr. Jacquemont and his team have also led and developed a series of controlled trials to evaluate experimental treatments for fragile X syndrome. These trials represent a paradigm shift and are among the first to assess a treatment targeting a specific molecular mechanism involved in a neurodevelopmental disorder.

Dr. Jacquemont and his team are also actively studying structural genomic variants (deletions and duplications) associated with autism and schizophrenia. Specifically, they investigate the effects of gene dosage on cognitive and behavioral symptoms, as well as endophenotypes such as neuroanatomy. They work with an international cohort of individuals carrying structural variants on chromosome 16 (16p11.2).

Awards and Distinctions

• 2015, Neuroscience Publication of the year, "La Recherche" Journal
• 2014, Canadian Research chair in genetics of neuro-developpemental disorders
• 2014, Jeanne et Jean-Louis Levesque fund in genetics of neuropsychiatric disorders

Presentations

• Rare variant genetic architecture of human cortical MRI phenotypes in general population. Society of Biological Psychiatry (SOBP), Austin, USA (2024)
• Rare variant genetic architecture of human cortical organization. Organization for Human Brain Mapping (OHBM), Seoul, South Korea (2024)
• The effect of non-recurrent CNVs on cognition and risk for psychiatric disorders.Fragile X and Autism-Related Disorders Gordon Research Conference, Lucca, Italy (2022) 
• Effects of gene dosage on brain, behaviour, risk for Autism and neurodevelopmental disorders. National Institute of Health Neuroscience Seminar Series, USA (2022)
• Predicting effects of CNVs on cognition and risk for psychiatric conditions. XXVe Colloque de l'Association des Cytogénéticiens de Langue Française (ACLF), Grenoble, France (2021).

Publications

1. Vorstman J., Sebat J., Bourque V-R, Jacquemont S. (2024). Integrative genetic analysis: cornerstone of precision psychiatry. Mol Psychiatry.
2. Schultz LM, Knighton A, Huguet G, Saci Z, Jean-Louis M, Mollon J, Knowles EEM, Glahn DC, Jacquemont S, Almasy L. (2024). Copy-number variants differ in frequency across genetic ancestry groups. HGG Advances.
3. Gur RC, Bearden CE, Jacquemont S, Swillen A, van Amelsvoort T, van den Bree M, Vorstman J, Sebat J. et al. (2024). Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications. Mol Psychiatry.
4. Kopal J, Huguet G, Marotta J, Aggarwal S, Osayande N, Kumar K, Saci Z, Jean-Louis M, Chai XJ, Ge T, Yeo BTT, Thompson PM, Bearden CE, Andreassen OA, Jacquemont S, Bzdok D. (2024). High-effect gene-coding variants impact cognition, mental well-being, and neighborhood safety substrates in brain morphology. medRxiv.
5. Schmilovich Z, Bourque VR, Douard E, Huguet G, Poulain C, Ross JP, Alipour P, Castonguay CÉ, Younis N, Jean-Louis M, Saci Z, Pausova Z, Paus T, Schuman G, Porteous D, Davies G, Redmond P, Harris SE, Deary IJ, Whalley H, Hayward C, Dion PA, Jacquemont S, Rouleau GA. (2024). Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability. Front Psychiatry.
6. Minhas A, Whitlock K, Rosenfelt C, Shatto J, Finlay B, Zwicker J, Lippe S, Jacquemont S, Hagerman R, Murias K, Bolduc FV. (2024). Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health. J Autism Dev Disord.
7. Kopal J, Kumar K, Shafighi K, Saltoun K, Modenato C, Moreau CA, Huguet G, Jean-Louis M, Martin CO, Saci Z, Younis N, Douard E, Jizi K, Beauchamp-Chatel A, Kushan L, Silva AI, van den Bree MBM, Linden DEJ, Owen MJ, Hall J, Lippé S, Draganski B, Sønderby IE, Andreassen OA, Glahn DC, Thompson PM, Bearden CE, Zatorre R, Jacquemont S, Bzdok D. (2024). Author Correction: Using rare genetic mutations to revisit structural brain asymmetry. Nature Communications.
8. Rødgaard EM, Rodríguez-Herreros B, Zeribi A, Jensen K, Courchesne V, Douard E, Gagnon D, Huguet G, Jacquemont S, Mottron L. (2024). Clinical correlates of diagnostic certainty in children and youths with Autistic Disorder. Mol Autism.
9. Kopal J, Kumar K, Shafighi K, Saltoun K, Modenato C, Moreau CA, Huguet G, Jean-Louis M, Martin CO, Saci Z, Younis N, Douard E, Jizi K, Beauchamp-Chatel A, Kushan L, Silva AI, van den Bree MBM, Linden DEJ, Owen MJ, Hall J, Lippé S, Draganski B, Sønderby IE, Andreassen OA, Glahn DC, Thompson PM, Bearden CE, Zatorre R, Jacquemont S, Bzdok D. (2024). Using rare genetic mutations to revisit structural brain asymmetry. Nature Communications.
10. Gur R, Bearden C, Jacquemont S, Jizi K, Amelsvoort van T, van den Bree M, Vorstman J, Sebat J, Ruparel K, Gallagher R, Swillen A, McClellan E, White L, Crowley T, Giunta V, Kushan L, O'Hora K, Verbesselt J, Vandensande A, Vingerhoets C, van Haelst M, Hall J, Harwood J, Chawner S, Patel N, Palad K, Hong O, Guevara J, Martin CO, Bélanger AM, Scherer S, Bassett A, McDonald-McGinn D, Gur R. (2023). Neurocognitive Profiles of 22q11.2 and 16p11.2 Deletions and Duplications. Research square.