2025 ASXL Research Symposium

Speaker biographies and abstracts

Listed alphabetically by last name

Megan Abbott, MD

University of Colorado

Measuring Better: How we determine severity in neurogenetic conditions

  • Dr. Megan Abbott is a pediatric epileptologist at Children’s Hospital Colorado, embarking on a career in clinical research focused on outcome measures in developmental and epileptic encephalopathies (DEEs). She is working to establish new multi-disciplinary clinics, generate gene-specific datasets, and devise outcome measures applicable to various DEE populations. Having grown up with a brother with autism, she has both a personal and professional connection to working with rare disease families. She is excited to begin this work with the hope that we can advance further towards clinical trial readiness and disease modifying therapies for DEEs.

Valerie Arboleda, MD, PhD

UCLA

ASXL Research Symposium Program Committee

  • 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.

Karim-Jean Armache, PhD

NYU Grossman School of Medicine

Visualizing the Mechanisms of Epigenetic Inheritance and Regulation

  • Karim-Jean Armache, Ph.D., is the Laura and Isaac Perlmutter Professor of Biochemistry at NYU Grossman School of Medicine. His research focuses on the mechanistic basis of chromatin regulation, with emphasis on Polycomb and Trithorax group complexes, histone modifications, and the epigenetic control of gene expression. Using integrative approaches spanning structural biology, chemical biology, biochemistry, and cell biology, Dr. Armache’s lab has uncovered fundamental mechanisms of key chromatin‐modifying enzymes and identified new therapeutic opportunities in cancer and developmental disorders.

  • H2AK119 monoubiquitination (H2AK119ub) is a central chromatin modification deposited by Polycomb Repressive Complex 1 (PRC1), removed by BAP1/ASXL1, and recognized by DNMT3A1. Mutations in these complexes disrupt the dynamic balance of H2AK119ub deposition, removal, and recognition, leading to widespread epigenetic misregulation. These mechanisms place H2AK119ub at the core of developmental regulation and disease-associated chromatin dysfunction. I will present new mechanistic insights from our studies of these complexes.

Oliver Bell, PhD

Keck School of Medicine of the University of Southern California

Development of selective chemical probes targeting PRC1 functions

  • Oliver Bell obtained his PhD in the lab of Dr. Dirk Schuebeler at the Friedrich Miescher Institute in Basel, Switzerland, where he studied the distribution and function of active histone modifications. For his postdoctoral training, he joined the lab of Dr. Gerald Crabtree at Stanford University, developing a reductionist approach to study the kinetics and inheritance of heterochromatin in living cells. In his own laboratory, Dr. Bell employs genetics and chemical biology approaches to investigate how heterochromatin regulators control cell identity in development and in disease.

  • Dysregulation of Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2) is associated with various human malignancies, including cancer. While PRC2 has been the primary focus of pharmaceutical research, our lab’s objective is to develop chemical probes that can specifically antagonize different PRC1 activities. Validated and selective PRC1 antagonists could provide unique insights beyond conventional genetic techniques to enable mechanistic exploration and assess preclinical target validity, motivating future drug development efforts and impacting patient care.

Stephanie Bielas, PhD

University of Michigan

ASXL Research Symposium Program Committee

Advisor, ARRE Foundation Medical and Scientific Advisory Board

  • 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.

University College Dublin

ASXL Research Symposium Program Committee

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. 

Tomasz Cierpicki, PhD

Department of Pathology, University of Michigan

Discovery of small molecule inhibitors of Polycomb Repressive Complex 1 as novel therapeutic agents

  • Dr. Cierpicki is a Professor in the Department of Pathology at the University of Michigan. His research interest is in the area of chemical biology and cancer epigenetics. Current focus of his research is development of small molecule inhibitors for novel and challenging proteins in cancer. His laboratory discovered first-in-class inhibitors of menin as well as other epigenetic proteins including PRC1, NSD1 and GAS41.

  • Polycomb Repressive Complex 1 (PRC1) is a key epigenetic regulator that controls gene expression by modifying chromatin structure, primarily through monoubiquitination of histone H2A. We have developed first-in-class small-molecule inhibitors of PRC1 that bind to RING1A and RING1B, leading to a global reduction of H2Aub in cells. Treatment of multiple leukemia cell lines with these inhibitors results in potent growth inhibition, induction of differentiation, and in vivo efficacy. These findings highlight the potential of PRC1-targeting small molecules as novel therapeutic agents.

Lucy Doyle

University of Edinburgh

Investigating the importance of H2AK119ub balance and Polycomb subunit expression dynamics during neurodevelopment

  • Lucy Doyle is a PhD student in the Illingworth lab at the University of Edinburgh. Her research focuses on how epigenetic regulators, including PRC1 and PR-DUB, control neural stem cell fate and early brain development. Using a combination of biochemical approaches, single-cell and spatial transcriptomics, she investigates how changes in H2AK119ub and Polycomb subunit expression impact lineage specification and cortical organisation, with implications for understanding neurodevelopmental disorders.

  • H2AK119 monoubiquitination, deposited by PRC1 and counteracted by PR-DUB, is a key epigenetic mark controlling neural stem cell self-renewal and differentiation. Overlapping human neurodevelopmental disorders caused by mutations in PRC1 and PR-DUB subunits implicate the importance of this balance, yet the precise role of H2AK119ub remains unclear. Using a hypomorphic RING1B mouse model, we show that reduced H2AK119ub disrupts neural progenitor identity, leading to inappropriate activation of non-neural transcription factor networks and developmental defects. Synthetic activation experiments support a model in which H2AK119ub acts as a molecular buffer against lineage-inappropriate transcription. PRC1 and PR-DUB exist as multi-subunit complexes with diverse compositions, but their functional specificity during neurodevelopment is poorly understood. To address this, we analysed single-cell datasets of mouse brain development and performed MERFISH spatial transcriptomics, revealing distinct expression patterns of various PRC1 and PR-DUB subunit genes, suggesting region- and cell type–specific roles. These findings provide insight into how catalytic activity, transcription factor interactions, and dynamic subunit composition may collaboratively maintain lineage fidelity and contribute to our understanding of mechanisms by which Polycomb dysfunction leads to neurodevelopmental disorders.

Kristina T. Johnson, PhD

Northeastern University

Language and communication for individuals with complex neurodevelopmental differences

  • Dr. Kristina (Kristy) Johnson is an Assistant Professor at Northeastern University, jointly appointed in Electrical & Computer Engineering and Communication Sciences & Disorders. Kristy received her Ph.D. in Affective Computing from MIT and was a postdoctoral fellow at Boston Children’s Hospital and Harvard Medical School in the Rosamund Stone Zander Translational Neuroscience Center. She also holds an M.S. and Honors B.S. in Physics. Her research focuses on individuals with complex neurodevelopmental differences, especially those with autism, intellectual disabilities, rare genetic disorders, and minimal spoken speech. She works at the intersection of science and engineering, specializing in personalized naturalistic studies, developmental science, digital healthcare, and augmentative technology. She is also the parent of a child with a rare genetic neurodevelopmental disorder and autism (MEF2C Haploinsufficiency Syndrome).

Thomas Koehnke, MD, PhD

Stanford University

Modeling ASXL1 mutations in primary human stem cells

  • After completing medical school at the University of Goettingen, Germany and research at Massachusetts General Hospital in Boston and the Charité University hospital in Berlin, Dr Koehnke completed his clinical training in Hematology/Oncology at the University of Munich, Germany. Following this, he trained as postdoctoral fellow in the laboratory of Ravi Majeti at Stanford studying ASXL1 mutant pre-leukemic evolution and progression into leukemia. He currently works at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford developing novel approaches to perform prospective genetic experiments directly in patient specimens.

  • Recent technological advancements have enabled us to conduct prospective, functional, genetic studies in primary human stem cell systems. These approaches allow us to move beyond purely descriptive studies in human primary cells, complementing functional interrogation of hypotheses in mouse and cell line studies. These techniques have provided valuable insights into the role of mutations in ASXL1 on stem cell function and offer opportunities to explore therapeutic approaches. In this talk, we will discuss strategies to interrogate the role of ASXL1 mutations on normal and malignant hematopoietic stem cells and which challenges remain.

Vijay Kumar M. J., MSc, PhD

University of Texas Health Science Center at Houston

The G-quadruplex helicase DDX5 regulates ASXL3 expression in human astrocytes

  • Dr Vijay Kumar M. J. is a postdoctoral researcher in the department of Neurology at McGovern Medical School, UTHealth, Houston, working in the laboratory of Dr. Andrey Tsvetkov. His research explores the molecular mechanisms of brain aging, with a particular focus on the role of G-quadruplex (G4) structures and G4 helicases in chromatin remodeling, epigenetics and neurological disorders.

    His work aims to uncover fundamental mechanisms by which G4 structures shape transcriptional programs and epigenetic states during aging. As a part of his research, he discovered that G4-resolving helicase DDX5 regulates ASXL3 expression, opening new directions for investigating the intersection of G4 biology with chromatin-associated genes implicated in neurodevelopmental processes.

    Dr Vijay's work bridges the field of G4 biology and chromatin dynamics with an emerging interest in how G4s may contribute to ASXL-related disorders

  • Guanine (G)-rich nucleic acid sequences in the human genome and transcriptome can fold into non-canonical secondary structures called G-quadruplexes (G4s or G4-DNA and G4-RNA). G4-DNA regulates replication, transcription, recombination, and telomere maintenance, while G4-RNA influences RNA processes including translation. However, overly stable G4-DNA induces genomic instability, and abnormally stabilized G4-RNA disrupts RNA-dependent functions. Numerous G4-binding transcription factors, G4-binding proteins (G4BPs), and G4 helicases interact with G4s and shape their cellular landscapes. The DEAD-box protein 5 (DDX5) is an ATP-dependent G4 helicase that resolves G4-DNA and G4-RNA and regulates transcription by unfolding promoter G4s. We found that G4 homeostasis is altered in aged human astrocytes, marked by increased G4s and reduced DDX5 expression. To define the transcriptional role of DDX5, we performed RNA-seq in primary human astrocytes from epilepsy surgeries. Of 14,821 genes measured, 460 were differentially regulated by DDX5: 214 upregulated and 246 downregulated, forming networks central to the cell cycle, p53 signaling, senescence, and longevity. Among the top hits was ASXL3, encoding a chromatin modifier and epigenetic regulator. Mutations in ASXL3 cause Bainbridge-Ropers Syndrome, a neurodevelopmental disorder with intellectual disability, seizures, and microcephaly. We observed an age-dependent decline in ASXL3 expression in human astrocytes, with significantly reduced levels in aged cells. Notably, ectopic DDX5 expression upregulated ASXL3 protein. We also identified putative G4-DNA motifs in ASXL3’s promoter and gene, suggesting DDX5 may promote ASXL3 transcription by unfolding G4s. Our study uncovers a novel mechanism of DDX5-dependent ASXL3 regulation, linking G4s to Bainbridge-Ropers Syndrome etiology and suggesting potential therapeutic strategies for this disorder.

Natasha Ludwig, PhD

Kennedy Krieger Institute and Johns Hopkins School of Medicine

ASXL Research Symposium Program Committee

Advisor, ARRE Foundation Medical and Scientific Advisory Board

Review of clinical research projects in ASXL-related disorders

  • 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 presentation will highlight key clinical research initiatives advancing the understanding of ASXL-related disorders. The ASXL Natural History Study, led by Dr. Bianca Russell, is building a foundational dataset to inform diagnosis, care, and future therapeutic development. Feeding into this effort are the ALPS Project, directed by Dr. Natasha Ludwig, which focuses on behavioral phenotyping to better characterize neurodevelopmental profiles, and the CHAMPION Study, led by Dr. Rujuta Wilson, which investigates autism symptoms and motor functioning in children with chromatinopathies. Together, these studies contribute critical phenotypic and functional data to the Natural History Study. Complementing these initiatives is a PCORI-funded focus group project that facilitated the development of an engaged network of diverse stakeholders and the implementation of community-based focus groups and survey. This effort has been instrumental in identifying and prioritizing patient-centered research questions across gastrointestinal, neurodevelopmental, and behavioral domains. Collectively, these initiatives are aligned toward a shared goal of clinical trial readiness.

Heather B McLean, PT, MPT, CBIS

Kennedy Krieger Institute

Gross motor observations from the 2024 ASXL Family Conference: A physical therapy perspective and introduction of the Physical Abilities and Mobility Scale (PAMS) in ASXL- RD

  • Heather McLean, PT, MPT, CBIS, C/NDT has over 34 years of experience in clinical practice as well as education and mentoring in both academic and clinical settings. Her pediatric clinical experience includes acute care (NICU, PICU, cardiac, orthopedic, neurosurgical, general medicine), multidisciplinary outpatient clinics, outpatient, and inpatient rehabilitation.

  • Physical Therapy (PT) is frequently a recommendation starting with early intervention, but often caregivers and professionals don’t appreciate the realm of pediatric PT. This presentation will take a look at PT-related opportunities for individuals with ASXL-RD. The Physical Abilities and Mobility Scale (PAMS), a gross motor function outcome measure, will be introduced as incorporated during the 2024 ASXL Family Conference.

Jürg Müller, PhD

Max-Planck Institute of Biochemistry, Munich

Functional analysis of the Asx C-terminal region and its interacting proteins in Drosophila

  • Jürg Müller studied biology at the University of Zürich where he received his PhD in 1991. For his post-doctoral studies, he joined the laboratory of Peter Lawrence at the MRC Laboratory of Molecular Biology in Cambridge. Jürg Müller has led his own research group since 1996, first at the Max Planck Institute for Developmental Biology in Tübingen and then at the European Molecular Biology Laboratory in Heidelberg. Since 2010 he is at the Max Planck Institute of Biochemistry in Munich. His lab studies the role of chromatin in transcriptional regulation in Drosophila, using genetics, biochemistry and structural biology.

  • The Polycomb Repressive Deubiquitinase (PR-DUB) complex functions as a major deubiquitinase that removes monoubiquitin from histone H2A at lysine 119 within nucleosomes (H2Aub1). Binding and deubiquitination of H2Aub1-modified nucleosomes depends on the interaction between the deubiquitinase adaptor domain (DEUBAD) of the PR-DUB subunit Asx and the catalytic subunit Bap1. The Drosophila Asx protein, encoded by a single-copy gene, and its mammalian paralogs ASXL1, ASXL2, and ASXL3 all share a conserved architecture: the N-terminal DEUBAD domain, followed by an extended low-complexity region (LCR) of more than 1000 amino acids, and a C-terminal PHD finger domain. While these C-terminal regions are not required for PR-DUB assembly or for H2Aub1 deubiquitinase activity in vitro, work in Drosophila suggests that they are essential for targeting PR-DUB to Polycomb-regulated genes in vivo. In flies, deletion of the entire Asx LCR together with the adjacent PHD finger results results in embryonic lethality through excessive H2Aub1 accumulation specifically at Polycomb target genes, disrupting their repression. We have investigated the role of the Asx C-term in Drosophila by generating diverse deletion mutants and by identifying proteins that interact with discreet sequence elements in this region of Asx. Progress in understanding the role of these interactions in shaping the H2Aub1 chromatin landscape and the regulation of PR-DUB target genes will be presented.

Julia T. O'Connor, PhD

Kennedy Krieger Institute and Johns Hopkins University

Qualitative analysis to understanding behavior challenges in ASXL-related disorders

  • Dr. Julia O'Connor is a research scientist and licensed psychologist at Kennedy Krieger Institute. She is the Associate Director of the Neurobehavioral Unit Outpatient Programs and an assistant professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. She completed her master's and doctoral training at the State University of New York in Binghamton in clinical psychology. Dr. O'Connor's research has focused on the assessment and treatment of severe behavior problems including self-injury, aggression, pica, property destruction and other problem behaviors exhibited by individuals with neurodevelopmental disabilities.

  • Provide an overview of the qualitative analysis process to analyze the outcome data from the parent focus groups highlighting the priority areas for families in relation to behaviors in ASXL. Development of focus group themes to formulate research questions. Top research questions will be highlighted.

Beate Peter, PhD, CCC-SLP

College of Health Solutions, Arizona State University

Knowledge is Power: How to foster speech and language skills of children with Bainbridge-Ropers syndrome using personalized and proactive strategies

  • Beate Peter, Ph.D., CCC-SLP, is an Associate Professor in the College of Health Solutions at Arizona State University. Peter heads the Speech/Language Genetics lab, which is home to three lines of research: genetic etiologies of communication disorders, gene-brain-behavior links in communication dis-/abilities, and early and proactive interventions for children at genetic risk for communication disorders. At Arizona State University, Peter established a Ph.D. concentration called Translational Genetics of Communication Abilities (TGCA) for future scientists who wish to train in a unique environment combining genome science, neuroscience, and communication behaviors. The Speech/Language Genetics Lab created a novel prophylactic speech/language intervention called Babble Boot Camp for infants who have a known genetic risk for speech and language disorders. As the first intervention of this type, Babble Boot Camp has been successfully trialed with infants with a newborn diagnosis of classic galactosemia. Subsequent trials are underway with infants who have other predictable risks for speech and language delays. The overarching theme of the work in the Speech/Language Genetics lab is translating some key principles of precision medicine, especially prophylaxis and personalization, into the world of speech-language pathology.

  • Difficulty learning to talk is one of the most common challenges faced by children with Bainbridge-Ropers syndrome (BRPS), and one of the most worrisome to their parents. According to the literature, children with BRPS either do not develop spoken language at all, or their verbal communication is delayed or disordered; however, detailed descriptions of speech and language have not been provided. Here, for the first time, we present the speech and language trajectories of two brothers with BRPS, for whom developmental coordination disorder underlies motor processes across domains. We show how understanding one sibling’s childhood apraxia of speech informed his speech and language therapy, resulting in remarkable progress, and how understanding the motoric limitations for the other resulted in a comprehensive functional communication system. We also showcase two unrelated infants with BRPS whose parents participated in ten months of weekly Babble Boot Camp sessions. Babble Boot Camp is a prophylactic speech and language intervention that we developed for infants at predictable risk. These four cases all exemplify successfully translating core principles of precision medicine (personalization; prevention) into the world of speech-language pathology.

Michael Rauchman, MDCM

Washington University School of Medicine

Diverse Mechanism of Developmental Defects in Townes-Brocks, an Autosomal Dominant Syndrome

  • Michael Rauchman, MDCM is Chromalloy Professor of Medicine and Professor of Developmental Biology and Pediatrics at the Washington University School of Medicine. He is a physician-scientist with clinical specialty training in nephrology (kidney disease). Dr. Rauchman directs a pediatric-to-adult transition clinic for patients with kidney disease, which provides care for many individuals with neurodevelopmental disorders including autism. His laboratory investigates mechanisms of gene regulation by transcription factors and their associated chromatin-remodeling complexes during kidney development and disease. Ongoing studies focus on cell fate specification of nephron progenitor cells during formation of the embryonic kidney, and growth and maturation of the kidney from birth through adolescence. We apply this knowledge to understand the basis of birth defects of the kidney and childhood kidney disease. A second area of emphasis is investigation of epigenetic mechanisms in response to kidney injury that promote tissue repair versus progressive fibrosis leading to kidney failure. To advance knowledge in these areas of study, his lab uses multiple genomic technologies (single cell RNA/ATAC-seq, spatial transcriptomics, chromatin profiling with CUT&RUN & ChIP-seq, Hi-ChIP) to interrogate genetically engineered mice, rodent models of injury and human kidney tissue samples.

  • Truncating mutations in SALL1 cause Townes-Brocks, an autosomal dominant syndrome characterized by congenital anomalies affecting multiple organs. SALL1 mutation associated phenotypes are caused by loss-of-function, dominant negative and dominant interference effects on other SALL family proteins. These studies may inform genetic mechanisms of other dominant disorders due to truncating mutations, such as syndromes due to ASXL gene mutations. Ongoing studies of human congenital anomalies of the kidney and urinary tract (CAKUT) identified ASXL3 as a novel CAKUT gene, thereby expanding the phenotypic spectrum of Bainbridge-Ropers syndrome.

Bianca Russell, MD

UCLA

ASXL Research Symposium Program Committee

Advisor, ARRE Foundation Medical and Scientific Advisory Board

  • 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.

Latha Valluripalli Soorya, PhD

Rush University Medical Center

Functional Behavioral Treatment (FBT) adaptations for Neurogenic Sydromes: one treatment, two targets

  • Latha Valluripalli Soorya, PhD is a clinical psychologist, board certified behavior analyst, Associate Professor, and Director of the AARTS Center a lifespan autism program in the Department of Psychiatry and Behavioral Sciences at Rush University Medical Center. Dr. Soorya specializes in complex neurodevelopmental conditions, focusing her clinical research and clinical care on social, emotional, and behavioral needs in neurodevelopmental conditions. Dr. Soorya is also active in teaching and service, holding positions on training faculty in several institutions and local advocacy and philanthropic boards.

  • This talk will provide an overview of WINGS: a Web Intervention for Parents of Youth with Genetic Syndromes. This NIH-funded trial is evaluating an adaptation of Functional Behavioral Treatment (FBT), an established challenging behavior intervention, for delivery by mental health professionals in speciality neurogenic clinics. FBT provides a framework for building coping skills while reducing challenging behaviors, addressing clinical and translational clinical trial needs. The presentation will provide an overview of FBT, rationale for adaptations, considerations for study populations, and lessons from early stages of the trial. Q & A will facilitate a discussion of how this work may support the ASXL community and considerations for adaptations in Bohring-Opitz Syndrome, Shashi-Pena Syndrome, and Bainbridge-Ropers Syndrome across development.

Wen-Hann Tan, BMBS

Boston Children’s Hospital

ASXL Research Symposium Program Committee

Advisor, ARRE Foundation Medical and Scientific Advisory Board

  • 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.

Lu Wang, PhD

Northwestern University

Decoding the BAP1 Complex: From Chromatin Regulation to Disease Pathogenesis

  • Lu Wang is an Assistant Professor of Biochemistry and Molecular Genetics at Northwestern University. He obtained his Ph.D. from Nanjing University in China in 2011. He then completed his first postdoctoral training in cancer biology with Dr. Wei Xu at UW Madison, followed by a second postdoctoral training in cancer epigenetics with Dr. Ali Shilatifard. In 2019, he started his independent research career at Northwestern University. His lab focuses on understanding the genetic and epigenetic abnormalities involved in human diseases, identifying potential therapeutic targets, and developing novel therapies for treatment.

  • The BRCA1-associated protein 1 (BAP1) functions as a general transcriptional activator by catalyzing the removal of histone H2AK119 mono-ubiquitination deposited by PRC1. Dysregulation and mutations of the BAP1 gene and its associated factors have been identified as drivers of developmental and metabolic diseases, as well as various human cancers. Here, we will discuss the regulation of the BAP1 complex and explore how its dysfunction contributes to disease development.

2024 ASXL Research Symposium

Speaker biographies and abstracts

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.

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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