The first international clinical guideline for Kleefstra syndrome

For families living with Kleefstra syndrome, a common problem is not only the complexity of the condition, but also the absence of a shared care plan. Different doctors may know different aspects of the syndrome, while some healthcare professionals may encounter it for the first time. The first international, evidence-based clinical guideline attempts to bridge this gap by offering an organized framework for diagnosis, monitoring, management of individual problems, and family support.

The directive was published online on January 20, 2026, at Genetics in Medicine and it concerns Kleefstra syndrome type 1, meaning the form caused by pathogenic variants in EHMT1 or by deletions of chromosomal material involving this gene. It is not a study of a new treatment. It is a clinical guideline development project, aimed at translating available scientific data and the collective experience of experts and families into practical guidance.

A common framework with 66 recommendations

Forty-three clinical experts and patient representatives from 15 countries participated in the development of the guideline. The team conducted a systematic literature search and combined the findings with expert and patient consensus procedures. The result is 66 specially tailored recommendations that cover the individual's needs across different ages and multiple organ systems.

The need for such a broad framework is linked to the role of EHMT1. The gene encodes an epigenetic regulator, meaning a protein that helps control how other genes are used. When the function of EHMT1 is insufficient, neurodevelopment, communication, behavior, sleep, and other functions can be affected, as well as the heart, hearing, vision, growth, the gastrointestinal tract, and metabolism. The clinical picture varies from person to person, which is why the guideline outlines a minimum common level of organized care without assuming that everyone needs the same tests.

Topics include diagnostic investigation and genetic counseling, neurological monitoring and epilepsy, sleep, mental health, and behavior. Communication, speech therapy, and alternative and augmentative communication, such as sign language, pictures, or communication devices, are also included. These tools do not mean the abandonment of spoken language; they can expand the possibilities for expression and participation.

Monitoring of development and mental health

Of particular importance is the recommendation for structured behavioral and mental health assessment at the time of diagnosis and at least once a year. Regular reassessment can help the clinical team recognize changes early, rather than automatically attributing every new symptom to the underlying diagnosis. The guideline also examines the regression of previously acquired skills, such as loss of speech, self-care, mobility, social participation, or other functions. This refers to a loss of skills and not to gastroesophageal reflux.

Other sections cover hearing and vision, cardiological care, development, obesity and metabolic issues, as well as gastrointestinal problems. The transition from pediatric to adult services and family support are treated as essential parts of care rather than secondary issues. The approach is lifespan-oriented because needs and priorities change with age.

Within the appropriate diagnostic framework of a neurodevelopmental disorder, the guideline supports the use of genome or exome sequencing as a first-line genetic test. This does not mean that a specific test is appropriate in every case. The selection and interpretation of the genetic test remain clinical decisions made on the basis of history, examination, and genetic counseling.

What is changing for families today

The immediate value of the publication is that families and clinicians now have a common, internationally developed point of reference. The guideline can be used in discussions with pediatricians, geneticists, neurologists, psychiatrists, cardiologists, therapists, and adult care teams. It can be particularly useful where local professionals lack prior experience with Kleefstra syndrome, because it helps organize priorities and routine monitoring.

The guideline specifically concerns EHMT1-related Kleefstra syndrome type 1. Conditions historically described under other names, such as certain KMT2C-related disorders, are genetically distinct and should not be automatically considered equivalent. The international panel plans to review the guideline every five years so that recommendations can be adjusted as clinical data increase.