Active family participation has begun in the longitudinal study on Kleefstra syndrome

A family report published by IDefine on October 19, 2025 confirmed that the longitudinal study on the course of Kleefstra syndrome at Boston Children’s Hospital has now moved from the planning stage to active family participation. The visits described in the report took place in September 2025 and included comprehensive evaluation at the hospital, as well as home-based monitoring of certain parameters.

This is what is internationally called natural history studya systematic, longitudinal study that monitors how a condition manifests and evolves over time, without administering any experimental treatment.

In other words, this specific research it is not a clinical treatment trial. It is not testing any drug, gene therapy, or RNA intervention. Its goal is to gather reliable data on the development, behavior, sleep, health, and daily functioning of individuals with Kleefstra syndrome.

For families, such a study may initially seem less important than a therapeutic trial. In reality, however, it constitutes one of the essential steps needed before future clinical trials can be properly designed.

Researchers must first know which features of the syndrome can be measured reliably, how these change with age, and what changes could be considered meaningful for both the individual and their family.

Who can participate and what does the study include

The study, led by Dr. Siddharth Srivastava, involves individuals aged 2 to 21 years with a confirmed pathogenic variant in EHMT1, the gene associated with Kleefstra syndrome type 1.

In Kleefstra syndrome, usually one of the two copies of EHMT1 does not function normally or is absent, resulting in one functional copy not being sufficient for the normal function of the gene. This condition is scientifically described as haploinsufficiency (haploinsufficiency).

The study design provides for the participation of a total of 30 individuals over a three-year period. Each participant is scheduled to undergo one evaluation per year for three years, meaning a total of three annual visits.

Special emphasis is placed on the participation of children aged 2 to 11 years, as to date there is less data on the course of the syndrome in younger ages.

The basic procedures of the study include:

• neurodevelopmental and neurobehavioral assessments,
• questionnaires completed by parents or caregivers,
• review of medical history,
• medical examination,
• interviews with parents or caregivers.

Neurobehavioral evaluations can take approximately two to four hours. Completing the questionnaires may require a total of about two hours, while parent interviews are estimated to last from one to two hours.

There are also optional parts of the study, such as blood draws, photography, home sleep recording with a Fitbit device, and an electroencephalogram (EEG) for children aged 2 to 11 years.

The electroencephalogram records the electrical activity of the brain. Its inclusion in the research protocol does not mean that the child necessarily has epilepsy; it may be used for research purposes to study characteristics of brain function.

What is a research visit like in practice

The family experience published in October 2025 provides a more practical picture of what participation in the study may involve.

The described visit took place over two half-days and included approximately 3.5 hours of neurobehavioral assessments, an electroencephalogram, recording of physical and biometric data, blood collection, and at-home sleep monitoring.

This description is particularly useful for families, as it shows that participation may require a significant amount of time and cooperation from the child or young person.

These procedures may be more demanding for individuals with sensory difficulties, complex communication needs, behavioral problems, mobility limitations, or other health issues. It is therefore expected that not all participants will be able to complete all assessments in the same way.

The available study information states that in-person visits are preferred, while in some cases remote monitoring may be possible when travel is not feasible.

Financial support of $500 for travel expenses is also mentioned after each completed in-person visit.

However, as seat availability, participation requirements, and recruitment status may change, interested families should confirm current information directly with the research team or IDefine.

Why is it so important to know the natural history of the syndrome

In an extremely rare and highly heterogeneous syndrome, it is difficult to properly evaluate the efficacy of a future treatment if we do not first know how the condition progresses without it.

Children grow and develop, some skills may improve with appropriate support, while other characteristics may change naturally with age. At the same time, two individuals with alterations in the same gene, the EHMT1, may have very different needs, capabilities, and developmental trajectories.

Repeated evaluation of development, cognition, behavior, sleep, communication, daily functioning, and other characteristics can therefore help researchers decide what exactly they should measure in a future clinical trial.

These measurable characteristics are called outcome indicators (outcome measures). They may, for example, relate to communication, self-care, sleep, behavior, or an electroencephalogram characteristic.

An outcome measure is not in itself a measure of «cure.» It is a predefined way in which researchers can assess whether and to what extent a specific function has changed.

Similarly, the study can contribute to the search for potential biomarkers. A biomarker is an objectively measurable biological characteristic that can provide useful information for research. It is not necessarily a diagnostic test, nor does it mean that the specific characteristic will become a therapeutic target.

Combining genetic, clinical, and laboratory data with each participant's age and course can help researchers identify which measures are reliable and sensitive enough to be used in future therapeutic trials.

What we know to date

Family experience confirms that studying has now been put into practice and that families are actively participating in evaluations.

The projected sample of 30 individuals remains relatively small, although this is not unusual when studying such a rare syndrome. At the same time, the participants are likely not to fully reflect the entire spectrum of individuals with Kleefstra syndrome in terms of geographic origin, socioeconomic background, symptom severity, or the complexity of their medical needs.