RORA gene related neurodevelopmental disorders are rare, complex, and often misunderstood.

Together, we can change that.

A female scientist using a microscope in a laboratory, with another scientist taking notes nearby.

What We Can Answer Today

  • What is the RORA gene?

    RORA (retinoic acid-related orphan receptor alpha) is a gene that produces a protein that helps regulate the activity of other genes. It plays a key role in brain development, especially in the cerebellum, which is responsible for coordination and balance. The RORA gene also supports neurological health by helping protect neurons from stress and inflammation.

  • What happens when there’s a change in the RORA gene?


    Certain rare pathogenic variants in RORA disrupt its normal function. These changes can interfere with brain development and lead to a condition known as RORA-related neurodevelopmental disorder. This rare condition is caused by variations in a single copy of the gene (autosomal dominant) and has been observed in multiple unrelated families around the world. It can occur de novo, which means it is non-inherited.

  • What are the symptoms of a RORA-related disorder?


    Research shows that RORA-related variants can cause developmental delays, with many children walking and talking later than typical. Intellectual disability and autism spectrum disorder features affecting learning, social interaction, and communication are common. About half of individuals experience epileptic seizures, often generalized or myoclonic. Poor coordination (ataxia) is also frequent due to cerebellar dysfunction, leading to unsteady walking, low muscle tone, and balance difficulties; MRI scans often show cerebellar underdevelopment, particularly of the vermis. Symptoms vary widely in severity and may appear early or develop over time.

  • What are potential symptoms needing more research?


    Some additional features have been reported in individuals with RORA variants or are biologically plausible, but current evidence is still limited. These may include ADHD and executive function challenges, emotional dysregulation and behavioral challenges, and sensory processing differences like sensitivity to sound, touch, or visual stimuli. Sleep disturbances are also possible, since RORA helps regulate circadian rhythms, but direct clinical evidence in individuals with RORA-related disorder remains limited and more research is needed.

  • Why does research into RORA matter?


    Although there is currently no cure, ongoing research is uncovering how RORA functions in the brain and what might go wrong when it’s disrupted. Preclinical studies are exploring potential treatments that could one day enhance RORA activity or protect neurons, offering hope for future therapies.

    Understanding RORA is not only helping affected individuals and families — it’s also shedding light on broader mechanisms in autism, epilepsy, and brain health.

What’s possible?

Over the past few years, science has taken a major step forward in understanding RORA-related neurodevelopmental disorders. What was once completely uncharted territory is now a recognized medical condition with defined causes and symptoms — and the momentum is only growing.

While there is still no cure, researchers are working actively to uncover how RORA affects the brain and how we might intervene. The path won’t be easy, and there are still many unknowns. But the arc of science is bending toward discovery — and toward hope.

Today

  • Earlier diagnoses and intervention

  • Improved symptom management and better clinical care guidelines

  • Dedicated research on natural history and functional studies

Tomorrow

  • Research discoveries

  • Therapeutic innovations

  • Preclinical drug testing

Future

  • Gene therapy to correct or compensate for defective genes

  • Precision and personalized medicine

The research to date.

  • What We Learned: Report of the largest series of individuals with RORA-related-neurodevelopmental disorder. The RORA-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.

    Our Research Heroes: Mariagrazia Talarico, Julitta de Bellescize, Matthias De Wachter, Xavier Le Guillou, Guylène Le Meur, Matthieu Egloff, Bertrand Isidor, Benjamin Cogné, Diane Beysen, Paul Rollier, Melanie Fradin, Laurent Pasquier, Ilaria Guella, Scott E. Hickey, Paul J. Benke, Amelle Shillington, Candy Kumps, Olivier Vanakker, Erica H. Gerkes, Shenela Lakhani, Irina Romanova, Ilya Kanivets, Melanie Brugger, Katharina Vill, Raymond C. Caylor, Cindy Skinner, Rory J. Tinker, Tommy Stödberg, Astrid Nümann, Tobias B. Haack, Natalie Deininger, Holger Hengel, Jeanne Jury, Solène Conrad, Sandra Mercier, Grace Yoon, Melissa Tsuboyama, Giulia Barcia, Cyril Gitiaux, Marlène Rio, Andrea Bevot, Sylvia Redon, Kevin Uguen, Antje Wonneberger, Alexander Schulz, Dagmar Timmann, Danielle Hays Karlowicz, Nicolas Chatron, Amanda Carnevale, Sonal Mahida, Katrin Õunap, Sébastien Kury, Sara Cabet, Gaetan Lesca.

    Publication: Genetics in Medicine, Volume 27, Issue 4, 2025, 101347, ISSN 1098-3600.

    Links:

    https://doi.org/10.1016/j.gim.2024.101347

    https://www.sciencedirect.com/science/article/pii/S1098360024002818

  • What We Learned: Demonstrated that AAV-delivered RORA gene therapy was effective and well-tolerated in a mouse model of Stargardt disease, showing potential for broader therapeutic use.

    Our Research Heroes: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA: M. Akula, S. M. McNamee, Z. Love, N. Nasraty, N. P. M. Chan, M. Whalen, M. O. Avola, A. M. Olivares, B. D. Leehy, A. S. Jelcick, D. F. Chen & N. B. Haider, and Ocugen, Inc., Malvern, PA, USA: P. Singh & A. K. Upadhyay

    Publication: Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD. Gene Ther 31, 413–421 (2024).

    Links:

    https://doi.org/10.1038/s41434-024-00455-z

  • What We Learned: Mutations in the RORA gene are now confirmed to cause a range of brain-related disorders in humans, depending on the type and location of the mutation.

    Our Research Heroes: Claire Guissart, Xenia Latypova, Paul Rollier, Tahir N. Khan, Hannah Stamberger, Kirsty McWalter, Megan T. Cho, Susanne Kjaergaard, Sarah Weckhuysen, Gaetan Lesca, Thomas Besnard, Katrin Õunap, Lynn Schema, Andreas G. Chiocchetti, Marie McDonald, Julitta de Bellescize, Marie Vincent, Hilde Van Esch, Shannon Sattler, Irman Forghani, Isabelle Thiffault, Christine M. Freitag, Deborah Sara Barbouth, Maxime Cadieux-Dion, Rebecca Willaert, Maria J. Guillen Sacoto, Nicole P. Safina, Christèle Dubourg, Lauren Grote, Wilfrid Carré, Carol Saunders, Sander Pajusalu, Emily Farrow, Anne Boland, Danielle Hays Karlowicz, Jean-François Deleuze, Monica H. Wojcik, Rena Pressman, Bertrand Isidor, Annick Vogels, Wim Van Paesschen, Lihadh Al-Gazali, Aisha Mohamed Al Shamsi, Mireille Claustres, Aurora Pujol, Stephan J. Sanders, François Rivier, Nicolas Leboucq, Benjamin Cogné, Souphatta Sasorith, Damien Sanlaville, Kyle Retterer, Sylvie Odent, Nicholas Katsanis, Stéphane Bézieau, Michel Koenig, Erica E. Davis, Laurent Pasquier, Sébastien Küry.

    Publication: Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia, The American Journal of Human Genetics, Volume 102, Issue 5, 2018, Pages 744-759, ISSN 0002-9297.

    https://doi.org/10.1016/j.ajhg.2018.02.021

    https://www.sciencedirect.com/science/article/pii/S0002929718300892

    1. Sidman RL, et al. (1962) – The staggerer mutant mouse: cerebellar degeneration due to Rora mutation.

    2. Wang Y, et al. (2009) – RORA expression in autistic brain and regulation of autism-related genes.
      PMID: 19567220

    3. Jetten AM. (2009) – Retinoid-related orphan receptors (RORs): roles in development, immunity, circadian rhythm, and metabolism.
      PMID: 19470374

    4. Molnár Z, et al. (2021) – Cerebellar hypoplasia in neurodevelopmental disorders: clinical and MRI findings.

    5. OMIM #618060 – RORA-Related Neurodevelopmental Disorder
      OMIM entry

    6. Nguyen A, et al. (2020) – RORA as a candidate gene in attention-deficit/hyperactivity disorder: insights from neurogenetics.
      PMID: 31993372

    7. Labonte B, et al. (2014) – Sex-specific differences in depression and RORA regulation.