ASXL Research Symposium

Speaker biographies and abstracts

Listed alphabetically by last name

University of Montreal

Moderator: Pathogenesis of ASXL-related disorders

El Bachir Affar, PhD

  • El Bachir Affar, PhD, in physiology-endocrinology, is the director of the Cellular Signaling and Cancer Research Unit at Maisonneuve-Rosemont Hospital. He is also a full professor in the Department of Medicine and an accredited professor in the Department of Biochemistry and Molecular Medicine at the Université de Montréal.

    Dr. Affar's research interests include cell signaling via ubiquitination, DNA and chromatin related processes (transcription and DNA repair), and the molecular basis of cancer. His team is particularly interested in the BAP1 gene, a gene that is frequently mutated in certain types of cancers.

UCLA

Metabolic dependencies of ASXL1 mutations

Valerie Arboleda, MD, PhD

  • I am a physician-scientist trained in human genetics, genomics and clinical pathology.

    The overarching research goals in my lab is to integrate large-scale data sets to improve our biological understanding and clinical treatment of human disease. In no other time in human history do we have such rich biological and clinical data, the bioinformatics tools to explore these relationships on a large scale, and the molecular genetic tools to rapidly experimentally validate findings in model systems.

  • Abstract to come

University of Toronto

Using the BOS-specific DNA methylation signature for classification of inherited and early truncating variants in the ASXL1 gene

Zain Awamleh, PhD

  • I am postdoctoral research fellow in the laboratory of Dr. Rosanna Weksberg at The Hospital for Sick Children in Toronto. My postdoctoral research has focused on developing DNA methylation signatures for the ASXL genes and the associated disorders. The signatures serve as a diagnostic biomarker that can support the diagnostic odyssey of patients and their families. I will be starting my laboratory genetics and genomics fellowship at SickKids in July 2024.

  • Our research group has previously identified a DNA methylation signature specific to Bohring-Opitz syndrome (BOS) caused by truncating variants in the last two exons of the ASXL1 gene. We have since identified a number of individuals with inherited variants in ASXL1, as well as individuals with truncating variants early in the ASXL1 gene, not typically associated with BOS. We demonstrate the diagnostic utility of the BOS DNAm signature through classifying the DNA methylation profiles of these individuals. We will also provide an update on the development of a Shashi-Pena syndrome signature which is caused by pathogenic variants in the ASXL2 gene.

ARRE Foundation

Welcoming remarks

Laura Badmaev

  • Laura is the Founder and Chair of the ASXL Rare Research Endowment Foundation and mother of Alex, who has Bohring-Opitz Syndrome (ASXL1). She is passionate about supporting evidence-based research and improving management of care for ASXL families. Laura grew up in the New York metropolitan area and eventually relocated to southern Maine where she lives with her husband, Michael, and their children, Alexander, Abigail, and Natalia. She is the first person in her family to attend college and has a B.S. in Operations Research & Industrial Engineering from Cornell University, and a Masters in Systems Engineering and Graduate Certificate in Engineering Management from Stevens Institute of Technology. She has completed a Certificate in Leadership Excellence from Harvard and is certified in Scaled Agile Framework as well as Six Sigma. Laura worked for the Department of Defense as an Integrated Logistics Support Manager and Research & Development Systems Engineering Advisor for several years. After completing her masters degree, she changed careers to work for American Express where she has served in various consultative and capability development roles for over a decade. American Express recognized Laura with the 2018 Top 10 Global Parent of the Year Award, 2019 Mother of the Year for Working Mother Media’s 100 Best Companies, and 2021 Chairman’s Award. Laura enjoys traveling and building relationships with individuals from around the world and learning about different cultures.

ARRE Foundation

Welcome from the Chief Scientific Officer

David Bettoun, PhD

  • Dr. David Bettoun joined the ARRE Foundation team in 2024 as the organization’s first Chief Scientific Officer. Dr. Bettoun brings over 20 years of broad experience in the biotech/pharmaceutical industry, with a proven track record in drug discovery and development. Most notably, he served as Vice-President of Discovery and Non-Clinical Research & Development at Larimar Therapeutics, where he led the development of innovative treatments for rare neurodegenerative diseases. Under his scientific leadership, Larimar advanced a first-in-class asset for the treatment of Friedreich’s Ataxia from early preclinical stages through IND-enabling studies and into clinical development.

    Dr. Bettoun holds a PhD in Physiology from McGill University. He lives with his family in Pennsylvania.

University of Michigan

1: Overview of ASXL-related disorders
2: ASXL neuropathology: Doubling down on repression

Moderator: Polycomb biology in model systems

Stephanie Bielas, PhD

  • Dr. Stephanie Bielas is the Morton S. and Henrietta K. Sellner Professor in Human Genetics and Associate Professor of Human Genetics and Pediatrics at the University of Michigan Medical School. Research in her lab focuses on discovering the genetic basis of human neurodevelopmental disorders. The Bielas lab performs functional follow-up using mammalian models of neural development, including primarily mouse models and human forebrain organoids. The Bielas lab has revealed novel features of human brain development and pathogenic mechanisms that are critical for developing therapeutic interventions. Dr. Bielas serves as a scientific advisor to Leo’s Lighthouse Foundation and ASXL Rare Research Endowment Foundation. Dr. Bielas also serves a principle investigator building clinical and research infrastructure to improve access to pediatric genetic diagnostic testing in India. This highly impactful research has been critical for identifying founder variants, with the direct impact of reducing testing cost, expanded availability of genetic testing to potential carriers and highlighting therapeutic targets.

  • Abstract to come

Food and Drug Administration

Understanding patient-focused drug development: A regulatory overview

Michelle Campbell, PhD

  • Dr. Michelle Campbell is the Associate Director for Stakeholder Engagement and Clinical Outcomes in the Office of Neuroscience, Office of New Drugs (OND) in FDA’s Center for Drug Evaluation and Research. Dr. Campbell joined the FDA in 2014 and previously was a reviewer on the Clinical Outcome Assessments (COA) Staff and Scientific Coordinator of the COA Qualification Program in OND.  Dr. Campbell’s focus is in patient-focused drug development and the use of patient experience data in the regulatory setting. Prior to joining FDA, Dr. Campbell spent more than 10 years conducting research in the academic-clinical setting, including five years in a neurology and developmental medicine department. Dr. Campbell earned her BA in Biology from the College of Notre Dame, her MS in Health Science from Towson University, and her PhD in Pharmaceutical Health Services Research from the University of Maryland School of Pharmacy.

University College Dublin

1: Histone H2A ubiquitination in chromatin structure, transcription and health

2: Mammalian polycomb: A complex story

Eric Conway, PhD

  • Dr. Conway completed his PhD in 2017 in Prof. Adrian Bracken’s lab at Trinity College Dublin. His Doctoral work focused on defining the function of a new vertebrate-specific family of Polycomb Repressive Complex 2 proteins, called PALI1 and PALI2. For his Post-doc, Dr. Conway joined Prof. Diego Pasini’s group at the IEO in Milan where he worked primarily on the contribution of H2AK119ub1 to transcriptional repression and chromatin compaction. This work focussed in particular on the tumour suppressor BAP1 and how to target BAP1-null cancers. Dr. Conway returned to Ireland in 2022 to establish his own research group at UCD focused on the mechanisms of chromatin architecture dysregulation in human disease. Dr. Conways lab focuses on establishing the molecular mechanisms of chromatin and transcriptional regulation. Mutations in epigenetic regulators that control these processes often drive human disease such as cancer and neurodevelopmental syndromes. This includes a major focus on the role of mutations in ASXL1 which can cause acute myeloid leukemia and Bohring-Opitz syndrome. The group uses next-generation genomics and molecular biology techniques such as Hi-C, Hi-ChIP, STORM, CUT&Tag, ChIP-seq and RNA-seq to explore the function of these epigenetic regulators. The ultimate aim is to understand the pathological role of these proteins in order to improve patient treatment. 

  • Histone H2A ubiquitination at lysine 119 (H2AK119ub1) is a critical mediator of transcriptional repression. This post-translation modification is deposited by Polycomb Repressive Complex 1 (PRC1) and erased by the Polycomb Repressive Deubiquitinase (PR-DUB) complex. Variants in the genes encoding subunits of these complexes are found in rare human developmental disorders. In particular, the catalytic subunit BAP1 features loss of function mutations in cancer while the ASXL1-3 subunits have nonsense and frameshift variants in developmental syndromes.

    Our work to date has revealed the mechanism of action of the PR-DUB complex. Using embryonic stem cells we show that BAP1 activity restricts H2AK119ub1 deposition to Polycomb target sites. Loss of PR-DUB function results in a broad increase in H2AK119ub1 levels that is primarily dependent on PCGF3/5-PRC1 complexes. This titrates PRC2 away from its targets and stimulates H3K27me3 accumulation across the genome, leading to chromatin compaction. This provides evidence for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo.

  • This talk will provide an overview of Polycomb biology in mammalian model systems, primarily focussing on mouse and human models. Within this we will discuss the composition and conservation of subunits of the Polycomb complexes (PRC1, PRC2 and PR-DUB) during vertebrate evolution. Mechanistic roles of the many Polycomb subcomplexes and specific subunits will be discussed including their roles in chromatin recruitment and catalytic activity. Common methods of studying Polycomb biology in mammals will be summarised including stem cells, in vivo and cancer models systems. Current approaches to perturb Polycomb function through chemical and genetical means will also be discussed.

UCLA

Neural signatures of neurodevelopment disorders: Insights from EEG spectral analysis

Abby Dickinson, PhD

  • Dr. Abigail Dickinson is an Assistant Professor of Psychiatry and Behavioral Sciences at the University of California, Los Angeles. She specializes in developmental neuroscience and employs high-density electroencephalography (EEG) to explore behavioral and cognitive variation in neurodevelopmental disorders, including Bohring-Opitz syndrome, Angelman Syndrome, and autism. Dr. Dickinson has developed innovative signal processing methods to characterize neurophysiological markers of these disorders, with a particular focus on identifying differences in functional network development related to cognitive ability and changes. Her research is dedicated to creating inclusive methods and techniques that are suitable for a broad range of children with neurodevelopmental disorders, including young infants and individuals with severe language or cognitive delays. Dr. Dickinson is especially interested in widely applicable EEG markers that can be collected in community settings to better understand risk/resilience factors and inform neural-risk markers for early services. Dr. Dickinson received her Master's degree in Cognitive and Computational Neuroscience and her Ph.D. from the University of Sheffield (UK). She joined UCLA in 2016 as a postdoctoral fellow and has since established her own laboratory focused on using EEG to understand developmental changes across the lifespan. Her work is particularly aimed at identifying markers that can help understand neural mechanisms and promote developmental outcomes across various neurodevelopmental conditions. 

  • EEG spectral analysis is a crucial tool for monitoring early brain development and elucidating brain dynamics in neurodevelopmental disorders. This presentation will introduce new findings from quantitative EEG metrics collected from 29 children diagnosed with Bohring-Opitz Syndrome. We will discuss both shared and unique neural signatures within this group and explore variations linked to neurodevelopmental outcomes and genetic profiles. Our results underscore the significant role of EEG metrics in advancing our mechanistic understanding of the common and distinct pathways linked to complex developmental trajectories.

Johns Hopkins University

Weaver syndrome and the path toward a targeted epigenetic therapy for abnormal skeletal growth

Jill Fahrner, MD, PhD

  • Dr. Jill Fahrner is an Associate Professor in the Departments of Genetic Medicine and Pediatrics at the Johns Hopkins University School of Medicine. She is a physician- scientist with a long-standing interest in epigenetic mechanisms of disease. She is Director of the multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins where her clinical focus is on caring for individuals with epigenetic and chromatin disorders. She has helped to delineate the Mendelian disorders of the epigenetic machinery (Chromatinopathies) as a distinct group and has seen hundreds of individuals with these conditions, most of which involve intellectual disability and abnormal growth. The goal of her laboratory research is to understand disease mechanisms and develop therapies for these disorders, including Weaver, Sotos, and Kabuki syndromes 1 and 2. She has led the field in establishing mechanisms for abnormal growth and identified a potential epigenetic therapy to treat overgrowth. She recently delineated the first neurodevelopmental disorder of the DNA demethylation machinery, Beck-Fahrner Syndrome. She earned her PhD in Cellular and Molecular Medicine from Johns Hopkins and her MD from the University of North Carolina, and she completed Pediatrics residency training at Duke University Medical Center. She completed Clinical Genetics residency training and served as Chief Resident in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins before joining the faculty. She is a long-standing member of the American Society of Human Genetics, having won an ASHG Reviewer’s Choice Abstract Award for her work on Kabuki syndrome 1, and she currently serves on the ASHG Program Committee, on the editorial board of the American Journal of Medical Genetics Part A, on multiple rare disease medical and scientific advisory boards, and on a National Organization for Rare Disorders (NORD) working group. She has received a Johns Hopkins School of Medicine Clinician Scientist Award, a Musculoskeletal Pilot and Feasibility Award, a William and Ella Owens Medical Research Foundation Award, the Margaret Ellen Nielsen Fellowship Award, and a prestigious Hartwell Foundation Individual Biomedical Research Award. Her research is supported by a National Institutes of Health (NIH) K08 Career Development Award, a Maryland Stem Cell Research Fund Launch Award, and Johns Hopkins University Catalyst and Discovery Awards.

  • Like the ASXL disorders, Weaver syndrome is a Mendelian disorder of the epigenetic machinery, or chromatinopathy. The cardinal phenotypic features of Weaver syndrome are generalized skeletal overgrowth, intellectual disability, and characteristic facial features. I will present our work elucidating the skeletal overgrowth phenotype in our novel Weaver syndrome mouse model, as well as its molecular basis. We have shown that Weaver mice exhibit excess osteogenesis in vivo and in vitro and that the transcriptional profile supports this mechanism. Treatment of osteoblasts derived from the Weaver mice with the drug GSKJ4 substantially reverses the transcriptional profile and the cellular phenotype of excess osteogenesis, suggesting a potential targeted therapy.

University of Edinburgh

Balancing histone ubiquitination in brain growth and development

Moderator: Regulation of gene expression

Rob Illingworth, PhD

  • Whilst studying Molecular Biology at the University of Edinburgh, Rob became fascinated by chemical modifications that could alter the functionality of DNA; a field known as epigenetics. This led Rob to embark on a PhD project with Sir Adrian Bird to develop novel biochemical tools to isolate DNA based on its methylation status. The timely advent of next generation sequencing provided a means to deep profile these isolates and, in so doing, to produce amongst the first genome-wide DNA methylomes from human and mouse cells. During this early phase of what is now known as ‘genomics’, a lack of analytical tools led Rob to develop his computational skills. He then leveraged this combination of genomics and bioinformatics in the lab of Prof. Wendy Bickmore in the MRC Human Genetics Unit. This postdoctoral research focussed on understanding the contribution of polycomb repressive complex 1(PRC1) structural and catalytic functions during early mammalian development. Through this work, Rob started to unpick the requirement for different functions of this essential regulator in the control of developmental gene expression in mammalian cells. In 2018, Rob established his lab in the Centre for Regenerative Medicine (CRM) and the Simon’s Initiative for the Developing Brain (SIDB) in Edinburgh. The Illingworth lab investigates how chromatin-based mechanisms control gene expression programmes to balance the need for cellular expansion and specification, and how derailing these processes leads to pathology. 

  • ‘Balancing histone ubiquitination in brain growth and development’ 

      

    During brain development, Polycomb proteins control the spatiotemporal expression of neurodevelopmental regulators to restrict cell fate decisions. Polycomb repressive complex 1 (PRC1) and polycomb repressive deubiquitinase (PR-DUB) act together to control the genomic abundance and distribution of the histone modification H2AK119ub1. The importance of this mark is underscored by the growing number of neurodevelopmental disorders (NDDs) attributed to impaired PRC1 and PR-DUB function. We use in vitro and in vivo model systems in combination with functional genomic approaches to investigate the consequences of alerted H2AK119ub levels on gene regulation and brain development. 

ARRE Foundation

Welcoming remarks

Amanda Johnson

  • Amanda joined the ARRE Foundation in 2021 as the organization’s first staff member. She leads the activities that support the ARRE Foundation’s mission of advancing research and improving quality of life for families living with ASXL-related disorders, including fundraising, programs, events, and partnerships.

    Amanda brings over 15 years of experience in donor-centered fundraising, event management and nonprofit administration experience to the ARRE Foundation. In previous roles, she served at the Pulmonary Hypertension Association, DC Central Kitchen, and the ARVO Foundation for Eye Research. She holds a BS in Organizational Communication from Ithaca College and an MA in Nonprofit Management from the Notre Dame of Maryland University. Amanda is originally from Western New York and lives in Maine with her family.

RIKEN Center for Integrative Medical Sciences

Polycomb silencing in development and homeostasis

Haruhiko Koseki,PhD

  • I graduated from Chiba University School of Medicine in 1986 and obtained PhD degree at Chiba University Graduate School of Medicine in the field of Immunogenetics in 1990. I did my postdoc in Max-Planck Institute of Immunobiology in Freiburg and then was appointed as a professor in Chiba University in 1998. In 2001, I was appointed as a Group director in RIKEN Center for Allergy and Immunology and have been a deputy director of RIKEN center for Integrative Medical Sciences since 2013. Meanwhile, my research has been focused to elucidate how mammalian Polycomb system functions during development. 

  • Polycomb silencing in development and homeostasis 

     

    Haruhiko Koseki, RIKEN-IMS 

     

    Polycomb group (PcG) factors form at least two distinct multimeric protein complexes, PRC1 and PRC2. In mammalian cells, PRC1 and PRC2 are mainly targeted to development/differentiation-related genes containing CpG islands (CGIs) and contribute to their silencing by mediating histone H2AK119 mono-ubiquitination and H3K27 trimethylation, respectively. PcG-target genes often exhibit dynamic changes in their expression during developmental process. KDM2B is a core component of PRC1 and recognizes CGIs by CxxC motif. KDM2B also possesses F-box and stably forms complexes with SKP1A, which potentially links PRC1 with Ubiquitin-Proteasome system (UPS). SKP1A bound to CGIs via KDM2B is shown to contribute to evict PRC2 by linking them with UPS in receipt of activating signals and activate PcG-silenced genes. 

University of Newcastle

A patient-centred disease concept model to capture what matters to individuals with Bainbridge Ropers Syndrome and their families

Isabelle Lecreps

  • Isabelle is a final year medical student from the University of Newcastle, Australia. She is currently completing her last term in an area of severe healthcare worker shortage in remote Australia. After simultaneously completing two Master degrees in engineering, one at the University of Lille and the other at the Technical University of Compiègne in France, she started her career as a process engineer in Germany. In 2011, she was awarded highest distinction from the Technical University of Munich for her PhD entitled ‘Physical mechanisms involved in the transport of slugs during horizontal pneumatic conveying’. In 2010, she accepted a position of engineer, lecturer, and research fellow at the University of Newcastle in Australia. She is first author of over 30 publications in the field of engineering and has contributed to the publications of several Australian Industry Standards. Since 2015, she is Director of a private engineering and consulting company. In 2017, she decided to refocus her research effort to medicine and in 2020, the University of Newcastle awarded her high distinction as well as the Faculty Medal for her achievements in the Bachelor of Biomedical Science. A few minutes later, she was admitted into medical school. She continues both her professional activities full-time. In her free time, she enjoys creating gardens, working on her farm, and hosting community events. This paper is her first paper in the field of medicine and genetics. 

  • We conducted a qualitative research study to characterise the experience of patients with BRS and their main caregivers and develop a patient-centred conceptual model of BRS that captures the key symptoms and impacts of the disease. The model highlights the disease heterogeneity and complexity whilst offering clinicians a different, caregiver-based perspective of the disease to consider for effective patient management. Patient-relevant outcomes are also given particular consideration when developing therapeutic drugs for rare diseases. The model will assist with the clinical management of BRS, development of targeted therapies, and delivery of appropriate support services. 

Kennedy Krieger Institute and Johns Hopkins School of Medicine

Deep phenotyping: Data collection efforts at ASXL Family Conference

Moderator: Clinical outcome measures

Natasha Ludwig, PhD

  • Dr. Natasha Ludwig is a clinical neuropsychologist and Program Director of the Developmental Neuropsychology Phenotyping Unit at Kennedy Krieger Institute. She is also an Assistant Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. Dr. Ludwig serves patients with a wide variety of medical and neurodevelopmental conditions from birth through adulthood primarily with an identified or presumed genetic etiology. Her research focuses on measurement of cognitive and functional skills in individuals with genetic conditions associated with neurodevelopmental disorders (GCAND). Dr. Ludwig is also the sibling of an adult with Bainbridge-Ropers Syndrome (ASXL3) and shares the lived experience of many of the families in our community.

  • This talk will provide information about the importance of deep behavioral phenotyping in advancing clinical care and research for ASXL-related Disorders. An overview of research-related activities at the conference and how this fits within the ASXL-Related Disorders Natural History Study will also be provided.  

University of Miami Miller School of Medicine

Missense mutations on PRC1 encoding genes deregulate neurogenesis

Lluis Morey, PhD

  • Dr. Morey is a Tenured Associate Professor at the Human Genetics Department at University of Miami and member of the Cancer Epigenetics Program at Sylvester Comprehensive Cancer Center. He received his degree in Biology from Universidad de Barcelona in 2003. He completed his PhD studies in the laboratory of Dr. Luciano Di Croce, where he studied the role of the chromatin-remodeling complexes in leukemia. He then joined Dr. Kristian Helin’s laboratory where he studied the role of non-coding RNAs in ESCs, and in 2010 he joined that Dr. Luciano Di Croce as staff scientist where he investigated the role of Polycomb complexes in ESCs. In 2016, he started his independent career as an Assistant Professor at UM. Dr. Morey has been the recipient of multiple grants from the American Association for Cancer Research, American Cancer Society, V Foundation, METAvivor and NIH-NIGMS and NIH-NCI among others. The lab’s focus is mainly on how chromatin modifying enzymes regulate oncogenic and developmental programs, and how perturbations of epigenetic pathways can be exploited for therapeutic interventions. 

  • Polycomb group (PcG) complexes are multi-protein, evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions, cell identity, and cancer. Interestingly, several PcG-encoding genes are also found to be mutated in individuals with neurodevelopmental disorders. I will present our efforts on the biochemical and biological characterization of missense mutations in genes encoding for RING1A and RING1B found in individuals with neurodevelopmental conditions. 

University of California San Francisco

Using frogs to investigate ASXL3 outside the nucleus

Christina Roca, BS

  • Christina Roca is a Neuroscience PhD student in Dr. Helen Willsey’s Lab in the Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco (UCSF). Christina has a B.S. degree in Behavioral Neuroscience & Natural and Applied Sciences from Florida International University. In the Willsey Lab, Christina is using diploid frogs (Xenopus tropicalis) to study large-effect risk genes for autism spectrum disorder, including ASXL3. One goal of her thesis work is to unravel the roles that ASXL3 plays in neurodevelopment outside of the nucleus. 

  • ASXL proteins are best known for their functions as chromatin regulators to control gene expression, acting through the “histone code” via methylation and/or ubiquitination of histones. However, many such proteins are known to be pleiotropic and also participate in the “tubulin code” via the same post-translational modifications of tubulin, thereby regulating microtubule stability. Microtubule regulation is particularly important for the formation and function of cilia, membrane-bound organelles present in almost all cells, including neurons. Cilia defects often cause many of the clinical presentations in ASXL-related disorders, therefore we hypothesize that ASXL proteins may have additional roles outside the nucleus, regulating microtubules in cilia. In this talk, we will demonstrate that patients with ASXL3 pathogenic variants often present with cilia-related conditions like congenital heart defects and that ASXL3 localizes to cilia in vivo using Xenopus. We will also present our recent progress investigating the possibility that ASXL3 regulates ciliary biology using this frog model, as well as our proposed future work in drug discovery.

UCLA

Updates from the ASXL Patient Registry and EEG study

Moderator: Systems biology approach to ASXL-related disorders

Bianca Russell, PhD

  • Dr. Bianca Russell is a clinical geneticist at University of California, Los Angeles (UCLA) who sees patients with metabolic and genetic conditions. She has been following patients with ASXL-related disorder since 2013 and has made this the research focus of her career. She started the ASXL Registry as a resident at Cincinnati Children's and expanded it to include a biobank when she transitioned to UCLA.

    Dr. Bianca Russell received her bachelors degree from Connecticut College in New London, Connecticut in 2008 and her medical degree from the University of California, Irvine in 2013. She completed her residency in Pediatrics and Human Genetics at the Cincinnati Children's Hospital in Cincinnati, Ohio.

  • Abstract to come

University of Toronto

Polycomb Repressive Complex 1 and histone H2A monoubiquitylation in C. elegans neuronal development

Arneet Saltzman, PhD

  • Arneet Saltzman is an Assistant Professor in the Department of Cell and Systems Biology at the University of Toronto. Her lab uses the model organism C. elegans to study how different layers of regulation work together to control gene expression and ultimately cell fate, development and epigenetic inheritance. Current projects use genetics, cell biology and genomics approaches to understand how chromatin regulators ensure robust neuronal development and maintain the immortality of the germline. 

  • PRC1 catalyzes histone H2A monoubiquitylation (H2Aub) and is essential for proper neuronal development. We are examining the impact of PRC1 mutations on chromatin state, gene expression, neuronal migration and behaviour in the nematode, C. elegans, a genetically tractable model organism with an invariant and well-described nervous system. Our genome-wide profiling reveals an unexpected enrichment of H2Aub at enhancers and suggests that PRC1 regulates neuronal enhancer activity. 

Duke University

An expanded clinical understanding of Shashi-Pena Syndrome

Vandana Shashi, MD

  • As a clinical geneticist for the last 27 years, I have worked with children and adults with various presentations of genetic disorders. When the diagnosis is not readily apparent, I have observed families invest inordinate amounts of effort, time and finances in an attempt to obtain a diagnosis. I evaluate patients with undiagnosed diseases and apply genomic sequencing to obtain diagnoses, to optimize medical management, and reproductive risk assessment. In 2017, a group of us described Shashi-Pena syndrome, due to truncating variants in ASXL2 [OMIM#617190] and I have been involved in enabling better clinical understanding of the condition and facilitating research into the condition.  

     

    I am the Principal Investigator of the NIH-funded Undiagnosed Diseases Network (UDN), Diagnostic Center of Excellence (DCoE) at Duke University. Overall, under my leadership the Duke UDN site has been responsible for diagnosing ~40% of patients and for 23 new published gene-disease associations that are associated with ultra-rare genetic disorders. The Duke DCoE has also led the network in studying the psychological toll associated with being undiagnosed and how patients perceive and utilize genomic sequencing results (genomic empowerment).  I am committed to increasing the access to genomic medicine for patients with health care disparities, having described that both practical barriers and low genomic knowledge are underlying factors for these individuals. Thus, factors extend beyond providing access to genomic medicine and requires community collaborations and outreach to providers and to patients, such that the patients are supported in a customized manner.  

      

    In addition to the experience in undiagnosed diseases, I have been a clinical researcher for many years, with a commitment to treatment of rare diseases utilizing the precision medicine paradigm. My other area of interest is chromosome 22q11.2 deletion syndrome (22q11DS). I have conducted studies of neuroimaging and behavior in 22q11DS and have been an investigator of the NIH supported International Brain and Behavior Consortium that analyzed clinical and genomic data from an international multi-site site on psychosis and the genomic underpinnings of this.  

     

  • Truncating variants in the ASXL2 gene result in Shashi-Pena syndrome, first described in 2017, in six individuals. Since then, further patients have been described across the world and we have a better understanding of the clinical findings, including neurodevelopmental manifestations in individuals with this ultra-rare disorder. While much more study is needed, we will provide a clinical update with an expanded number of diagnosed individuals 

Boston Children’s Hospital

Moderator: Clinical updates in ASXL-related disorders

Wen-Hann Tan, BMBS

  • Dr. Wen-Hann Tan a clinical geneticist at Boston Children's Hospital with an interest in diagnosis and management of rare genetic syndromes, including pediatric cancer predisposition syndromes, vascular malformations, and other unusual clinical findings. He has also been actively involved in a longitudinal natural history study and various clinical trials in Angelman syndrome, which is a rare neurodevelopmental disorder.

National Institute of Mental Health

Neurodevelopmental phenotyping for clinical trial readiness: Practices to consider from a developmental perspective

Audrey Thurm, PhD

  • Dr. Audrey Thurm, Ph.D. received training at DePaul University and Boston Children's Hospital/Harvard Medical School, and conducted a post-doctoral fellowship at Johns Hopkins School of Medicine. She has been at NIMH since 2002, serving in the extramural program until 2006, as chief of both the Autism and Social Behavior Program, and the Compulsive Repetitive Behaviors Program. In 2006 she moved to the intramural program to help launch the autism research program. She has expertise in longitudinal studies and an interest in markers of the early diagnosis of autism as well as genetic conditions associated with neurodevelopmental disorders. 

  •   

    This talk will focus on considerations from a clinical research perspective about what and how to measure specific areas of neurodevelopment.  We will discuss what is important to consider from early milestones all the way through domains that may be quite variable, such as communication and daily living skills.  We will discuss methods that may be helpful for current clinical use as well as for studies that capture the natural history of the condition as well as for treatment trials where specific regulatory requirements may constrain use of certain measures as outcomes. 

UCLA

Motor phenotyping in genetic neurodevelopemental conditions

Rujuta Wilson, MD

  • Dr. Rujuta B. Wilson is a behavioral child neurologist specializing in autism spectrum disorders and related neurodevelopmental disorders (NDDs). Dr. Wilson's clinical care and research also includes individuals with neurogenetic conditions. She is an Assistant Professor in Psychiatry and Pediatric Neurology at the UCLA David Geffen School of Medicine and the UCLA Center for Autism Research and Treatment (CART). Dr. Wilson leads the motor phenotyping core at UCLA CART and is part of the translational clinical core of the UCLA Intellectual and Developmental Disabilities Research Center (IDDRC). Dr. Wilson is also director of research for the UCLA Tarjan (UCEDD) Center. Dr. Wilson's NIH funded research is focused on developing quantitative methods of motor phenotyping in order to improve characterization of motor development in NDDs, better understand how motor impairments can impact cognition and language, and develop more targeted interventions for children with neurodevelopmental disorders. Dr. Wilson’s work also extends to measuring the physical and behavioral benefits of organized physical activity for children with NDDs. Dr. Wilson is an invited member of the United States Tennis Association Adaptive Committee. She is a member and past chair of the Child Neurology Society Leadership, Diversity, Equity, and Inclusion committee. Dr. Wilson has been selected several times as a Los Angeles Times Super Doctor, Southern California Rising Stars and as a Los Angeles Magazine L.A. Top Doctor. 

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Nationwide Children’s Hospital

The Inchstone Project:  Initial results from DEE Parents Speak Survey and future directions for outcome assessments

Mary Wojnaroski, PhD

  • Dr. Mary Wojnaroski received her bachelor’s degree in Psychology at Butler University and her master’s and doctoral degree in Clinical Psychology with a specialization in pediatrics at the University of Alabama. Dr. Wojnaroski completed an APA-accredited internship in at the University of Alabama in and a post-doctoral fellowship in Intellectual/Neurodevelopmental Disabilities at Nationwide Children’s Hospital. Mary Wojnaroski, PhD is a licensed clinical psychologist at Nationwide Children's Hospital and an Associate Professor of Pediatrics at The Ohio State University. She provides assessment and treatment of children and young adults with neurodevelopmental disabilities, including autism, ADHD, and cognitive delay. She has further specialization in assessment and treatment of children with neurodevelopmental conditions and epilepsy. Dr. Wojnaroski’s research and clinical interests have focused on early assessment and diagnosis of autism and other neurodevelopmental disabilities in children with epilepsy, developmental and behavioral assessment for children with severe to profound developmental disabilities, providing psychological and behavioral consultation for children with developmental disabilities during hospital admission, and behavioral intervention to increase compliance and comfort of children with neurodevelopmental disabilities in critical medical care. 

  • Neurodevelopmental or neuropsychological assessment is critical for individuals with medical and neurodevelopmental conditions, both for diagnosis and intervention planning.  Unfortunately, current assessment tools have limited ability to measure development and functional skills, and meaningful change in those skills, for individuals with Developmental and Epileptic Encephalopathies, including ASXL disorders.  This is especially true for individuals functioning in the severe to profound range.  The Inchstone Project is a team of family members, researchers, and clinicians dedicated to learning more about non-seizure outcomes that are important to families with DEEs and using that information to develop adequate and valid outcome assessments both for clinical trial and clinical practice.  This talk will review initial results from the DEE Parents Speak survey, which asked families about the most significant challenges and priorities for their family.  Challenges and future directions for outcome assessments in the DEE and ASXL community will also be reviewed. 

Sheffield Children’s Hospital/University of Sheffield UK

Updates from one year of an ASXL3 natural history study

Emily Woods, MBChB, MRCPCH

  • Emily is a Specialist Registrar in Clinical Genetics at Sheffield Children’s Hospital, UK. She gained her medical degree from The University of Birmingham, UK, and graduated in 2017. Emily’s background is in Paediatric medicine; she completed her post-graduate exams and became a member of the Royal College of Paediatrics in 2021. Emily has been working with Dr Meena Balasubramanian (consultant Clinical Geneticist in Sheffield, UK) for a number of years. Emily commenced her part-time research degree at The University of Sheffield in 2022. Over the last few years, Emily has joined the ASXL3-Balasubramanian Research Group and worked to get ethical approval for their ASXL3 Natural History Study, which opened for recruitment in late-summer 2023. Emily has since met with, and gained invaluable insight into, many ASXL3 families as part of this ongoing research study. Outside of work, Emily enjoys spending time with her husband and family. She enjoys long hikes in the near-by Peak District, and travelling to new places. 

  • The ASXL3-Balasubramanian research group, based in Sheffield (UK), have been working on ASXL3 for a number of years, and have already made significant contributions to the medical literature. Our Natural History Study for ASXL3-related disorder commenced in 2023. Since then, we have met with many families, obtaining deep phenotypic data. We aim to obtain longitudinal data over time. This presentation provides some insights into the Natural History Study, one year on.

Leiden Academic Centre for Drug Research

A holistic zebrafish model for Bohring-Opitz Syndrome: The gateway to high-throughput compound screening

Joey Zuijdervelt, MSc

  • As a PhD candidate under Micha Drukker at Leiden University, my research is centered on the molecular mechanisms of chronic pain in the peripheral nervous system. During my research internship in his group, I was introduced to the ASXL syndromes, specifically BOS (Bohring-Opitz Syndrome, associated with ASXL1 mutations). As a biologist by training, my aim then was to better understand the pathological mechanisms of the disorder in the context of early embryonal development. Although the main focus of my research now is on the role of the dorsal root ganglion in chronic pain, with the help of some very passionate undergraduate and graduate students I’m eager to keep moving our ASXL1 research forward. Currently, our students are developing ASXL1 reporter iPSC lines to improve protein detection, antibody validation, and the investigation of the role of ASXL1 in neural crest development. In parallel, they’re expanding our documentation of the BOS disease phenotype in zebrafish. As we approach this year’s ARRE symposium, we’re gearing up to explore new dimensions of our BOS zebrafish model. Our students will investigate the effects of ASXL1 truncating mutations on zebrafish neurulation and Epithelial-to-Mesenchymal Transition (EMT), alongside impacts on craniofacial development. Using computational modeling, they're also examining how these mutations affect ASXL1's functional domains. This work aims to provide a holistic zebrafish BOS behavioral model for screening symptom-mitigating compounds. Our approach harnesses computational tools like structural modeling, techniques such as bulk- and scRNA sequencing, and in vitro neural crest differentiation. Through this integrated research approach, we aim to uncover BOS pathology from its embryonic roots to therapeutic possibilities, and to pave the way for novel interventions that could significantly improve the lives of those affected by BOS and similar genetic conditions. 

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