What We Know About SETBP1-HD

SETBP1-HD is caused by changes in the SETBP1 gene, which plays a critical role in early brain development. Individuals with SETBP1-HD are haploinsufficient, meaning they have a loss of function in one copy of the gene, which results in the clinical manifestations of the disorder.

Thanks to years of collaboration between researchers, clinicians, and families, we now have a deeper understanding of the clinical spectrum of SETBP1-HD. In addition, scientists have developed cell lines and a growing number of animal models that are currently being characterized—crucial steps in identifying therapeutic targets.

We also recognize individuals who carry SETBP1 gene changes but present with overlapping features or uncertain molecular consequences. These individuals are classified as having SETBP1-related disorders (SETBP1-RD) and are a critical part of our research focus as well.

Our 2025 Research Strategy

To highlight our priorities and progress, we’ve developed a research strategy infographic (see above) outlining where we are now and where we’re headed. This framework reflects our current priorities as of May 2025, and emphasizes a full spectrum of research initiatives—from foundational discovery to real-world clinical application.

Key focus areas include:

• Foundational Science: Understanding SETBP1’s role in brain development and cellular function
• Model Development and Characterization: Utilizing cellular and animal models to uncover disease mechanisms
• Preclinical Research: Identifying and testing candidate therapies in laboratory settings
• Clinical Research: Designing and conducting studies that evaluate safety and effectiveness in humans
• Long-Term Monitoring: Building data systems and natural history studies to track outcomes over time

Each of these areas is essential to our long-term goal: identifying safe and effective treatments for individuals with SETBP1-HD.

Our Commitment

SETBP1 Society is deeply committed to transparency, collaboration, and education. We will continue to provide regular updates on our research strategy and actively support initiatives that move us closer to clinical solutions. Through strong partnerships and a unified community, we believe progress is not only possible—it’s already happening.

Together, we are SETBP1Strong.

Authored by Jordan Whitlock, PD – SETBP1 Society Science Coordinator

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2/26/25, Kelsey Bennett

In October 2024, nearly 100 clinicians, researchers, families, and supporters gathered in Austin, TX, for the first-ever SETBP1-HD conference, organized by the SETBP1 Society. This groundbreaking event aimed to deepen understanding of SETBP1 haploinsufficiency disorder (SETBP1-HD), facilitate on-site research, and explore future possibilities for individuals affected by this rare disorder. Inspired by a 2022 Simons Searchlight conference that united four rare disease groups, SETBP1 Society’s President, Haley Oyler, recognized the value in bringing SETBP1 families together for a focused gathering.

“There is nothing like being in the same room with fellow parents who get you and understand your journey. The experience was even more powerful with the opportunity to share it with researchers to help them deepen their understanding of how SETBP1-HD and related disorders impact our children. With the guidance of Simons Searchlight, SETBP1 Society was confident and prepared to host our first-ever SETBP1 conference.” said Oyler.

The event, held at the Cambria Hotel Uptown in Austin, was made possible by generous sponsorships from the Simons Foundation, Floyd Family, Elleco Construction, UltraGenyx, and Imprint. It provided an emotional and educational experience, allowing families to connect with researchers and share insights about living with SETBP1-HD, while learning about the latest advancements in the field.

Understanding SETBP1-HD

SETBP1-HD is a rare genetic disorder caused by a loss-of-function mutation in the SETBP1 gene, which is essential for normal brain function. Those affected typically have speech delays, developmental and intellectual disabilities, motor delays, autism traits/autism, ADHD, and other challenges such as seizures, feeding issues, anxiety, and sleep disturbances. SETBP1-HD is often the result of spontaneous (de novo) mutations, meaning there is no family history of the disorder.

Collaboration Among Experts

The conference began with a research-focused day where global experts shared their findings on SETBP1 research, including cellular models, mouse and zebrafish models, and enzyme replacement therapy. Researchers from institutions such as Vita-Salute San Raffaele University, Radboud University, and University of Texas presented on topics ranging from SETBP1 protein modeling to EEG biomarker studies, creating collaborative opportunities for future research.

Linda Bossini, a researcher at Vita-Salute San Raffaele University, emphasized the value of understanding clinical perspectives: “Gaining insights into the clinical aspects was incredibly valuable, helping us align our research with the needs and challenges faced in clinical practice.”

A Day for Families

The second day of the conference focused on the families and their experiences. Presentations included updates from the Simons Searchlight SETBP1 registry, with Dr. Cora Taylor sharing key data, and insights from Dr. Bregje van Bon on the SETBP1 Clinic in the Netherlands. Researchers also presented their progress on behavior assessments, animal models, cognitive evaluations, and EEG studies, with 12 patients participating in EEG screenings by the B-RAD team and onsite blood draws by Searchlight. These presentations were framed by updates on the SETBP1 Society’s progress, highlighting achievements from the past year and milestones that have been achieved since its founding in 2017.

A major focus of the conference was promoting independence for individuals with SETBP1-HD. A panel discussion featured advocates and experts like Steve Friedman, a parent, advocate, and author, alongside his independent daughter, Gwendolyn Friedman, special needs finance expert Barbara Bush and Monica Gelinas, founder of CC4C. They offered families valuable resources for fostering independence and supporting their loved ones.

Emotional Connections and Support

The conference also provided dedicated spaces for parents and grandparents to share their experiences. These breakout sessions focused on the unique joys and challenges of raising children with SETBP1-HD, with many discussions centered on educational support and school settings.

The day ended on a high note with a dance party, where families, researchers, and children celebrated the success of the conference. “The dance was pure joy. Watching all of the children just having a blast brought joy to my heart,” said Sonya Dearman, a grandmother of a SETBP1 “bee.”

Rare Disease Day

As Rare Disease Day approaches on February 28, 2025, the conference serves as a reminder of the importance of community, collaboration, and research in advancing care for those affected by rare disorders like SETBP1-HD. The SETBP1 Society’s first conference exemplifies how shared experiences and collective efforts can create a brighter future for individuals living with rare diseases, empowering them to live more independent and fulfilling lives.

To support SETBP1 research and families, visit https://givebutter.com/DonateSETBP1 or learn more at https://www.setbp1.org/.

Read the press release online

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Mice share more than 95% of our human DNA, meaning we are affected very similarly by disease. For over 90 years, The Jackson Laboratory has utilized this understanding to refine personalized medicine throughout the world and across a spectrum of diseases, now including SETBP1 disorder.

Austin, TX — November 23, 2020 — The SETBP1 Society began working closely with Cat Lutz, Ph.D. and Aamir Zuberi, Ph.D. of the Rare and Orphan Disease Center at The Jackson Laboratory (JAX), a nonprofit biomedical research institution, in 2018 to better understand how a mouse model could positively impact continued research and understanding of SETBP1 disorder.

This rare, monogenetic neurodevelopmental disorder causes the body to produce an insufficient amount of SETBP1 protein. In most instances, the variations in the SETBP1 gene are spontaneous and the families do not have a history of the disorder. The most common symptoms affecting those living with SETBP1 disorder are speech delay or inability to speak, intellectual disability, autistic traits or autism spectrum disorder, hypotonia, epilepsy, learning disabilities, and attention issues.

JAX’s Rare and Orphan Disease Center works with foundations like the SETBP1 Society to generate custom mouse models with clinical mutations to treat and cure rare and orphan diseases. Currently, the Center has worked in partnership with over 30 different rare disease foundations on mouse model development and has created models that provide greater understanding of the mechanisms of diseases such as Spinal Muscular Atrophy, Friedreich’s Ataxia, Rett Syndrome and ALS. Several alternate treatment options are being considered or developed as a result.

Over the last two years, JAX has successfully generated two model mice for SETBP1 research: a conditional knockout model (cKO) and an indel model. The cKO allele is modified from a previous allele generated by the global Knockout Mouse Programme (KOMP). The indel allele was generated using CRISPR/Cas9 technology.

“Ultimately, I think the models that we’ve generated are going to be really useful in getting a good handle on what SETBP1 does. The conditional knockout model is going to be a great way to evaluate not only the importance of SETBP1 in the brain, but how it works in different parts of the brain,” shared Zuberi, lead technology and resource development scientist at JAX. “Everything that we do leads us to a possible new direction that we can take. Generating a mouse model is the beginning of the process toward a therapy.”

Though it may take over a year to fully establish a new mouse model, once the mice are verified as having the intended disease or disorder, JAX then makes them available to interested researchers globally. This is a pivotal point in the development of treatments, as these researchers need effective tools to study the disease, and in the case of SETBP1 disorder, a necessary tool is the mouse model.

“A mouse model takes a rare disease and makes it common. We can develop a mouse model that our studies show accurately reflects the array of symptoms and phenotypes found in a clinical population, and now anyone can order that mouse strain anywhere in the world… any Ph.D. student, any postdoctoral associate, any researcher globally,” explained Zuberi. “By making that specific allele of a rare disease really common, we’ve now invited a huge community in to try different ways to fix it.”

As a direct result of the efforts of the Rare and Orphan Disease Center at JAX, the two model mice are now in the hands of a researcher at Baylor University in preliminary stages of research.

Haley Oyler, President of SETBP1 Society, said that the progress made toward researching this disorder simply would not have been possible without JAX. “The researchers at JAX took on the challenge and helped us shape our vision for the mouse models needed by intentionally consulting with our organization to develop the SETBP1 mouse models. We are confident that JAX is committed to our SETBP1 community and to the many other rare disorder communities they support! They are providing researchers the tools they need to answer the hard questions. Our partnership with JAX continues to bring us closer to a treatment to improve the lives of individuals living with SETBP1 disorder.”

For more information, press only:

Kelsey Bennett
402-619-8695
info@setbp1.org

For more information about the SETBP1 Society: https://www.setbp1.org

For more information about the Rare and Orphan Disease Center at the Jackson Laboratory:
https://www.jax.org/research-and-faculty/research-centers/rare-and-orphan-disease-center

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