Kleefstra Syndrome Clinic

• Principal investigator: Siddharth Srivastava, MD
• Co-investigator: Maya Chopra, MBBS, FRACP
• Co-investigator: Anne O’Donnell, MD, PhD 
• Co-investigator: Jonathan Lipton, MD, PhD
• Co-investigator: Joe Kossowsky, PhD, MMSc
• Research fellow: Muhammad Cagri Bayraktutan, MD
• Research manager: Zoë Frazier, MS, CGC
• Research coordinator: Meg Quinn, BA

Accelerating Clinical Trial Readiness Innovations for Monogenic Neurodevelopmental Disorders (ACTION) Initiative

Here at Boston Children’s Hospital, we are initiating a three-year longitudinal natural history study aimed at learning more about the clinical, molecular, and neurodevelopmental spectrum of Kleefstra syndrome. We aim to deeply characterize the full spectrum of features present with Kleefstra syndrome, and identify meaningful endpoints and biomarkers that can be used for future interventional trials.

To enroll, individuals must be between the ages of 2 to 21 years and have a diagnosis of Kleefstra syndrome. 

Study components

• Participants will complete three annual visits with the study team, which can be virtual or in-person.
• Neurobehavioral assessments and questionnaires will be completed at every visit.
• Participants will also be asked to complete a medical records release form to provide consent to review medical records from local clinics where they are receiving care. 
• Optional components:
  • Research EEG
  • Collection of a blood sample
  • Wearing a Fitbit at home for up to seven days, or as tolerated
  • Provide photographs

If you are interested in participating, have any questions, or would like more information, please feel free to contact our study team at 617-919-7370 or KleefstraSyndromeClinic@childrens.harvard.edu.

Circadian Biology of EHMT1

We conducted a research study for individuals ages 30 days and older diagnosed with Kleefstra syndrome and their parents/caregivers. In order to improve clinical care and better understand the frequently noted feature of sleep disturbance before regression, it is important to collect accurate information on sleep among individuals with Kleefstra syndrome. As such, the purpose of this research study was to gather detailed sleep and behavioral information, and learn more about the impact that EHMT1 has on the molecular pathways of sleep. We hope this will help us determine clinical care guidelines for treating sleep disturbance, regression, and mental health challenges associated with Kleefstra syndrome. 

Study components

• Parents/caregivers answered questions about their child’s behavior and sleep.
• Optional components:
  • Participants with Kleefstra syndrome had the option to wear a Fitbit device for a minimum of 14 days, or as tolerated.
  • Parents/caregivers completed a sleep diary during the time that the participant wore the Fitbit.
  • Both the healthy sex-matched biological parent and the participant diagnosed with Kleefstra syndrome (i.e., mother and daughter, or father and son) had the option to provide a blood and/or skin sample for the development of patient-derived cell lines.

Enrollment for this study is closed.

Investigating the Natural History of Kleefstra Syndrome

At Boston Children’s Hospital, we conducted a research study for individuals ages 13 years and older diagnosed with Kleefstra syndrome. In order to improve clinical care and prepare to carry out future clinical trials for individuals diagnosed with Kleefstra syndrome, it is important to collect accurate information on the effects and changes that happen (longitudinal natural history) among individuals with Kleefstra syndrome. As such, the purpose of this research study is to gather detailed historical and physical examination information on a large population of individuals with Kleefstra syndrome. We also hope this will help us determine clinical care guidelines for treating the mental health challenges such as psychosis and behavioral regression that can be associated with Kleefstra syndrome. 

Study components

• Parents/caregivers answered questions about the participant’s behavior and medical history.
• If participant showed clear signs of psychosis or a deterioration in behavioral functioning, the participant was asked to come in additional times.

Enrollment for this study is closed.

• Connors, K. L., Carmichael, N. E., Bichell, T. J., Dies, K. A., & Frazier, Z. J. (2025). Development of a Patient and Caregiver-Centered Pediatric Disease Concept Model for Kleefstra Syndrome. Sage Open Pediatrics, 12, 30502225251336880. https://doi.org/10.1177/30502225251336880
• Frazier, Z. J., Kilic, S., Osika, H., Mo, A., Quinn, M., Ballal, S., Katz, T., Shearer, A. E., Horlbeck, M. A., Pais, L. S., Dies, K. A., O’Donnell-Luria, A., Kossowsky, J., Lipton, J. O., Kleefstra, T., & Srivastava, S. (2025). Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome. Clinical Genetics. https://doi.org/10.1111/cge.14697
• Morison, L. D., Kennis, M. G. P., Rots, D., Bouman, A., Kummeling, J., Palmer, E., Vogel, A. P., Liegeois, F., Brignell, A., Srivastava, S., Frazier, Z., Milnes, D., Goel, H., Amor, D. J., Scheffer, I. E., Kleefstra, T., & Morgan, A. T. (2024). Expanding the phenotype of Kleefstra syndrome: Speech, language and cognition in 103 individuals. Journal of Medical Genetics, 61(6), 578–585. https://doi.org/10.1136/jmg-2023-109702
• Rots, D., Bouman, A., Yamada, A., Levy, M., Dingemans, A. J. M., de Vries, B. B. A., Ruiterkamp-Versteeg, M., de Leeuw, N., Ockeloen, C. W., Pfundt, R., de Boer, E., Kummeling, J., van Bon, B., van Bokhoven, H., Kasri, N. N., Venselaar, H., Alders, M., Kerkhof, J., McConkey, H., … Kleefstra, T. (2024). Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome. American Journal of Human Genetics, 111(8), 1605–1625. https://doi.org/10.1016/j.ajhg.2024.06.008
• Vasireddi, S. K., Draksler, T. Z., Bouman, A., Kummeling, J., Wheeler, M., Reuter, C., Srivastava, S., Harris, J., Fisher, P. G., Narayan, S. M., Wang, P. J., Badhwar, N., Kleefstra, T., & Perez, M. V. (2024). Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: A possible epigenetic link. Europace, 26(1), euae003. https://doi.org/10.1093/europace/euae003