At INSYNC-AS 2026, researchers came together to examine how genes beyond UBE3A and differences within UBE3A itself may shape Angelman syndrome and future therapeutic development.
Why can Angelman syndrome (AS) look different from one person to another, even when the diagnosis is the same? And could understanding those differences help researchers develop better treatment approaches for different Angelman syndrome genotypes? Those were the central questions at the 6th Annual International Angelman Syndrome Research Council (INSYNC-AS) Meeting, a collaboration between FAST and the Simons Foundation Autism Research Initiative (SFARI), FAST brings expertise from beyond Angelman syndrome to apply lessons and approaches from other areas of research to gaps in AS drug development. This year’s meeting, co-sponsored by Aligning Research to Impact Autism (ARIA), focused on how much of Angelman syndrome is explained by UBE3A alone, and what researchers may learn by looking more closely at genotype and specific genetic variants. Each year, INSYNC-AS brings together experts from the AS field along with those focusing outside of AS to focus deeply on a scientific question, or gap, that could help move research and therapeutic development forward, taking learnings from diverse drug development and research experiences. This year’s meeting centered on two primary goals:
Understanding the impact of genes beyond UBE3A that may contribute to differences seen between Deletion, UPD, and ICD Angelman syndrome genotypes, and identifying those additional genes and RNAs that may be most important to target therapeutically.
Exploring how different UBE3A variants may affect the function of the UBE3A protein and how that knowledge could help guide therapeutic development for Mutation AS.
Day 1: Looking Beyond UBE3A
UBE3A is the gene at the center of Angelman syndrome, but it is not always the only gene affected.
In Deletion AS, which is the most common genotype, a section of chromosome 15 is missing, which means UBE3A is deleted along with several neighboring genes. In UPD and ICD AS, paternal genes in the same region may be over-expressed, or duplicated. Both can result in genotype-specific symptoms and addressing those differences could be of great potential therapeutic benefit.
Researchers spent the first day asking an important question: how much do those other genes contribute to the traits and symptoms seen among individuals living with Angelman syndrome? And which genes may be most important to treat when there is a partial loss of function, or haploinsufficiency?
FAST Chief Science Officer Dr. Allyson Berent opened the meeting with an overview of the Roadmap to a Cure and the latest Angelman syndrome drug-development gap analysis. Dr. Elizabeth Berry-Kravis of Rush University Medical Center reviewed the current clinical trial landscape, including a high-level review of the ongoing ASO clinical trials, and the first gene therapy clinical trial in AS (ASCEND-AS). FAST’s Niki Armstrong shared an overview of phenotypic differences among Angelman syndrome genotypes.
What Researchers are Learning in Deletion AS
Researchers examined whether genes lost alongside UBE3A may help explain some of the differences seen between individuals living with Class 1 (larger deletion involving breakpoints 1-3) and Class 2 (slightly smaller deletions involving breakpoints 2-3) deletions and individuals living with other Angelman syndrome genotypes.
Dr. Anjali Sadhwani of @Boston Children’s Hospital shared data from the Angelman Syndrome Natural History Study comparing the two deletion groups and their subtle differences.
Dr. Art Beaudet of @Baylor College of Medicine provided key background on the genes located within the deletion region, helping frame which genes researchers may want to examine more closely.
Dr. Josef Kittler from @University College London reviewed the potential impacts of one allele deletion of the CYFIP1 gene.
Dr. Nathan Absalom of @Western Sydney University discussed the GABA-A receptors in Deletion AS, and how expression of the different GABA genes result in different symptoms, with GABRB3 being a strong candidate that may contribute to the seizure symptoms that are exacerbated in those with Class 1 or 2 deletions.
Dr. Shafali Jeste of University of California, Los Angeles shared learnings from 15q duplication syndrome, a related condition involving the same chromosome region that is duplicated and not missing. This was very informative to help understand which genes may be most likely to cause issues when overexpressed, highlighting the contribution of the overexpression of the GABA genes to UBE3A, rather than UBE3A alone being the only driver. Synergies between these two disorders was very clear and we will continue to collaborate to ensure we can advance the field for both as we learn.
What Researchers are Learning in UPD and ICD AS
The afternoon session focused on paternal genes that may be overexpressed in UPD/ICD AS, as well as examples of how other conditions have examined gene contributions:
Dr. Art Beaudet of Baylor College of Medicine again set the stage by summarizing the key paternally expressed genes in the region.
Dr. James Smith of University of East Anglia presented his work on SNORD116 and its potential contribution to UPD and ICD AS.
Dr. Sebastien Jacquemont of Sainte Justine Hospital Research Center shared research on multigenic effects and gene dosage, with the conclusion that genes within breakpoint 1 and breakpoint 2 may only contribute minimally to the Angelman syndrome phenotype.
The group also looked to Phelan-McDermid syndrome (PMS) for lessons on how researchers can study the effects of individual genes within a broader genetic condition that is also commonly associated with a segment that is deleted.
Dr. Joe Buxbaum of Icahn School of Medicine at Mount Sinai discussed work focused on SHANK3 and genetic variation in PMS, and he and Dr. Berry-Kravis reviewed how that understanding is being carried into the clinical trials, like a gene replacement therapy for a mini-gene of Shank3.
Day 2: Understanding What Different UBE3A Variants Actually Do
Day 2 focused on understanding how specific UBE3A variants (mutation AS) affect protein function, and how that knowledge could inform future treatment strategies for Mutation AS, as not all mutation result in a “loss of function” of the protein, and a protein is expressed that may interfere with a newly introduced healthy UBE3A copy.
Dr. Steve Traynelis from Emory University, Dr. Al George of @Northwestern University, and Dr. Kurt Haas of the University of British Columbia shared their approaches used in other genetic conditions to determine whether variants cause gain of function, loss of function, or a mix of functional effects. Understanding those differences can be an important part of drug development because they can influence how researchers think about potential treatment approaches, and who should be treated with a gene replacement, versus a gene knockdown or direct gene editing, for example. This is critically important to understand in the AS mutation variant population.
Dr. Seth Margolis of Johns-Hopkins University School of Medicine discussed UBE3A function and how mutations may affect the way the UBE3A targets other proteins, which ultimately may affect how the other proteins are degraded and overall neuronal function.
Dr. Yong-Hui Jiang, FAST-supported researcher at Yale University, shared work on several unique UBE3A variants that have an unexpected result on protein expression. His findings highlighted an important challenge: predicted effects in cellular or in silico assay do not always match what is observed when a variant’s impact on neuronal expression or protein function is tested in patient cell lines.
Dr. Jason Yi of @Washington University School of Medicine presented his work on UBE3A function determination as well as potential next steps for a broader, systematic analysis of the functional impact of UBE3A mutations.
The meeting concluded with a brainstorming discussion led by FAST CSO Dr. Allyson Berent and Dr. Ashley Winslow of Odylia Therapeutics, focused on identifying priorities and where research should go next.
Where the Research Goes from Here
Across both days, several important themes came into focus.
UBE3A remains central to Angelman syndrome, but it does not explain some of the differences seen across genotypes.
In Deletion, UPD, and ICD AS, other genes may also contribute to the clinical features researchers observe. FAST is supporting research using an approach called CRISPRa to increase the expression of other genes within Deletion AS. The research and discussions from INSYNC will guide which genes are prioritized for this project.
Understanding a UBE3A variant requires more than identifying that the variant exists.
In Mutation AS, researchers are working to better understand how specific variants affect protein function and whether those effects can be predicted reliably and influence the right therapeutic strategy for each individuals.
INSYNC-AS 2026 also helped identify where more data, tools, and collaboration are needed. The meeting concluded with researchers discussing which questions should be prioritized next and where focused research could have the greatest impact.
Want to follow where this research goes next? Visit FAST’s Industry & Research Hub to learn more about our scientific strategy and research priorities and join us a the FAST Science Summit on November 6-7 in Orlando Florida to hear scientific details around all the pre-clinical and clinical work currently being done to support AS drug development. Subscribe below for further research updates.