Kleefstra Syndrome The Kleefstra syndrome type 1 (KLEFS1) it is a rare genetic neurodevelopmental syndrome caused by reduced gene function EHMT1, which is located in the 9q34.3 region of chromosome 9. It affects the development and function of multiple body systems and varies greatly from person to person. Developmental delay and intellectual disability are common, as is childhood hypotonia, speech and communication difficulties, features of the autism spectrum, and certain recognizable facial and physical characteristics. Epilepsy, sleep disorders, hearing or vision problems, heart problems, constipation, metabolic difficulties, and mental health problems may also co-occur. However, no single individual necessarily exhibits all of these characteristics, and their severity varies significantly. In the late 1990s, the first individuals with this clinical picture were identified because they had a loss of genetic material at the end of chromosome 9. For this reason, the condition was initially described as «9q subtelomeric deletion syndrome», i.e., 9q subtelomeric deletion syndrome. In 2005, the discovery of an individual with a chromosomal rearrangement that specifically disrupted the EHMT1 indicated that this gene was likely the critical gene of the region. In 2006, the identification of pathogenic alterations directly within the EHMT1 confirmed that the loss of its normal function is the underlying cause of the syndrome. Thus it became clear that A large piece of chromosome 9 does not need to be missing for Kleefstra to be present. Today we know that about half of people with KLEFS1 have a pathogenic small variant within the EHMT1, while about the other half have a deletion or other copy number variation affecting the gene. A small percentage has more complex structural variations. Quick navigation What is EHMT1?; The most common features High variation from person to person Frequency of appearance Diagnosis Heredity Kleefstra syndrome type 2 EHMT2 and newer data Therapy Adulthood and life expectancy Then and now What is EHMT1?; The EHMT1 provides the instructions for the production of a protein that functions as epigenetic regulator. Along with the related protein EHMT2/G9a, it participates in the regulation of chromatin structure and the activity of many genes, among other things through the methylation of histone H3 at lysine 9. Simply put, it helps cells regulate which genes will be active, when, and to what extent. In KLEFS1 there is deficiency of a functional copy of EHMT1. The person usually has one functional copy, but the quantity or function of the protein produced overall is not sufficient for normal development and function. This is called haploinsufficiency – insufficiency of one functional copy. Because EHMT1 affects the regulation of many other genes during development, the consequences are not limited to a single organ. This helps explain why Kleefstra is a multisystem neurodevelopmental syndrome. The most common features The presentation of Kleefstra syndrome varies significantly from person to person. However, certain features occur much more frequently and form the core of the clinical picture. The 2026 international guidelines and GeneReviews cite as main features the developmental delay and/or intellectual disability, childhood hypotonia, speech and communication difficulties, autism spectrum features, and certain facial features. Developmental delay and intellectual disability Developmental delay is one of the most consistent features of KLEFS1. Intellectual functioning can range from mild difficulty to severe or profound intellectual disability. Older descriptions placed special emphasis on moderate and severe forms, but today we know that there are also individuals with a significantly milder cognitive profile. Hypotonia Η decreased muscle tone, especially in infancy and childhood, is very characteristic. It can contribute to delayed gross motor development, such as sitting, standing, and walking. Speech and communication delay Speech and language difficulties are very common. Expressive speech may be more affected than comprehension. However, the older view that most individuals with Kleefstra syndrome do not develop meaningful speech is now overly absolute: in the newer cohorts utilized in the 2026 guidelines, approximately 65% of individuals aged three and older were able to form sentences. Almost everyone who used spoken language had some speech disorder. Autistic traits and behavior Characteristics of the autism spectrum are very common. At the same time, stereotypies, adjustment difficulties, anxiety, mood swings, or other behavioral and psychiatric manifestations may appear. International guidelines state that overall behavioral or mental health problems have been recorded during the lifetime in approximately 74% of the individuals included in the available studies. Sleep disorders Sleep is one of the most frequent problems. Approximately 55% of the individuals in the studies included in the 2026 guidelines had sleep disturbances, primarily difficulty initiating or maintaining sleep. Constipation Constipation occurs approximately to half people with KLEFS1 and it can range from mild to very severe. Today it is considered an important part of the clinical picture, because it can simultaneously affect sleep, behavior, and general well-being. Hearing and vision problems Hearing problems have been reported in approximately 37% of individuals. Common vision problems are hyperopia and strabismus, while the possibility of cortical visual impairment (CVI) is now also recognized. Epilepsy Epilepsy is common but it is not available to everyone. The available studies give a fairly broad range, approximately 10%–44%, with different types of seizures and different age of onset. Weight Gain and Metabolic Problems Overweight and obesity are now recognized as a major and frequent feature, particularly in older children, adolescents, and adults. For this reason, the new guidelines place special emphasis on monitoring weight, metabolism, and thyroid function. Facial features There are certain morphological features that may make the syndrome recognizable to an experienced clinical geneticist. These may include brachycephaly, synophrys or prominent eyebrows, midface hypoplasia, a prominent lower jaw, and a characteristic lip shape. However, not everything appears in every person and they are not used on their own for diagnosis. Other co-occurring problems Renal and urological abnormalities, problems with the urogenital system, gastroesophageal reflux, feeding difficulties, respiratory problems and recurrent infections, dental abnormalities, and orthopedic problems. Their presence varies and A Kleefstra diagnosis does not mean that a child will exhibit all or even most of these symptoms. There is no “typical child with Kleefstra.”. The presence of one trait does not necessarily predict the presence of another, nor can a genetic diagnosis alone accurately predict a child's future course. High variation from person to person KLEFS1 does not have a single «typical» appearance. Cognitive function can range from mild difficulties to severe or profound intellectual disability. The same wide variation is observed in mobility, communication, behavior, autonomy, and medical needs. Even individuals with genetic alterations in the same gene can have a quite different course. The largest deletions including, besides EHMT1, and neighboring genes are associated on average with more medical problems and a more severe developmental presentation. However, this it does not allow an accurate prediction for a specific child solely from the size of the deletion or the type of the variant. Prevalence of the syndrome There is no global census of all people with KLEFS1 and the true frequency remains difficult to calculate. GeneReviews estimates that it may affect approximately 1 person per 25,000–35,000, while the 2026 international guidelines use an estimate of approximately 1 in 36,000. The actual frequency may be higher because quite a few people—especially those with a milder presentation—may remain undiagnosed. This represents a significant shift from the older perception that Kleefstra was an extremely rare syndrome affecting only a very small number of people with large chromosomal deletions. How is the diagnosis made today?; In the past, because the syndrome had initially been identified as a chromosomal deletion, the diagnosis was based primarily on tests such as FISH, karyotyping, chromosomal microarray, and subsequently targeted testing of the EHMT1. The 2026 international guidelines now recommend as first genetic test genome sequencing (GS) or, when this is not available, exome sequencing (ES), preferably as a trio —meaning a child and two parents— with the simultaneous capability of detecting copy number variations and structural rearrangements. If these techniques are not available, a chromosomal microarray may be performed first. In certain cases, more targeted monitoring of the EHMT1 the study of the characteristic epigenetic signature – episignature of the syndrome. A variant of uncertain clinical significance (VUS) alone is not enough to confirm the diagnosis. Is it inherited?; KLEFS1 follows primary mode of inheritance by descent through the body, but in most families the pathogenic variant appears again, meaning for the first time in the child. More rarely, gene or gonadal mosaicism, balanced chromosomal rearrangements in a parent, or familial transmission of a milder form have been described. Therefore, the risk of recurrence in a subsequent pregnancy It should not be automatically considered either 50% or zero.· calculated separately for each family after parental genetic testing and clinical genetic counseling. Prenatal and, where applicable, preimplantation genetic diagnosis can be discussed when the family's genetic variant is known. What applies to the so-called «Kleefstra syndrome type 2»?; This is a point where the terminology it has changed and older sources may be confusing. For several years, the OMIM database used the term «Kleefstra syndrome type 2» for a neurodevelopmental disorder caused by alterations in KMT2C. However, a large 2024 study of 98 individuals showed that KMT2C-related neurodevelopmental disorder is clinically and epigenetically distinct from classic Kleefstra syndrome caused by EHMT1. The 2026 international guidelines explicitly recognize that the name «Kleefstra syndrome type 2» for the KMT2C has created confusion and is limiting their recommendations exclusively to EHMT1-related KLEFS1. For this reason, on this website the term Kleefstra syndrome / KLEFS1 is used for the disorder caused by the loss of function of EHMT1. And what changes with EHMT2 in 2026?; In July 2026, a new study was published in Nature Communications which described seven individuals with de novo pathogenic variants in EHMT2. The clinical picture, certain epigenetic alterations, and cellular characteristics showed significant similarities with KLEFS1. The authors proposed the term «EHMT2-related Kleefstra syndrome». At the same time, however, the same study showed that the EHMT2-related condition has its own distinct epigenetic signature, therefore it is a distinct molecular entity closely related to KLEFS1 and not the same genetic syndrome. This development is very recent and does not change the 2026 international clinical guidelines for KLEFS1, which concern specifically the EHMT1. More cases and studies will be needed to fully define the clinical spectrum of EHMT2-related disorder. Is there a cure?; Today there is no approved treatment that restores EHMT1 or cures KLEFS1 as a genetic cause. Care is based on the early identification and management of individual needs: development, communication, sleep, epilepsy, mental health, vision, hearing, heart, metabolic health, gastrointestinal, and daily functioning. The 2026 international guidelines include a total of 66 clinical recommendations for lifelong care. At the same time, research has now begun to shift from simply understanding the syndrome toward therapeutic strategies that target the molecular mechanism itself. For example, in 2026 an academic research program was announced to increase EHMT1 production through programmable RNA activation. These approaches are still in preclinical research stage and do not constitute an available treatment. What do we know about adult life and life expectancy?; Scientific knowledge about adults with KLEFS1 is still less than the knowledge about children. This is also one of the reasons why the newer guidelines place special emphasis on lifelong monitoring and planned transition from pediatric to adult services. There is still insufficient long-term data to provide a reliable figure for life expectancy. Older reports have documented serious complications from congenital heart disease, aspiration, and recurrent pulmonary infections, but the data are insufficient to make generalizations for the current KLEFS1 population. What has changed compared to what we used to read in the past?; Today's picture of the syndrome is substantially different from the early descriptions: It was once considered primarily a «9q34 deletion syndrome». Very limited or absent speech was presented as an almost universal feature. The monitoring focused mainly on developmental delay, epilepsy, and congenital anomalies. The diagnosis relied more heavily on microarray, FISH, and targeted testing. the KMT2C was referred to as «Kleefstra syndrome type 2». Today… we know that KLEFS1 is caused by different types of alterations leading to a loss of its function EHMT1. we know that the communicative profile is much broader and quite a few people develop spoken language, although speech and language disorders remain very common. sleep, mental health, regression, constipation, obesity, and the transition to adulthood are considered key elements of care. Genome or exome sequencing, preferably as a trio and with the capability to detect structural variants, is the recommended first-line approach. Available data show that this is a distinct KMT2C-related neurodevelopmental disorder. Research is ongoing and the picture will continue to evolve. This is particularly important for such a rare syndrome, where many of the older percentages were based on small patient series. Even the 2026 guidelines point out that much of the available clinical literature remains of low-level evidence due to the small number of participants. Important clarification: This page is Greek informative review of contemporary scientific knowledge regarding Kleefstra syndrome type 1 (KLEFS1/EHMT1). It is not an official translation of the international guidelines and does not replace genetic counseling or personalized assessment by healthcare professionals. Latest scientific update: August 13, 2026 Basic scientific sources Bouman A. et al. International clinical evidence-based guideline for Kleefstra syndrome. Genetics in Medicine, 2026. Kleefstra T, de Leeuw N. Kleefstra Syndrome – GeneReviews®. National Center for Biotechnology Information. Kleefstra T. et al. Disruption of the gene Euchromatin Histone Methyl Transferase 1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome, 2005. Kleefstra T. et al. Loss-of-function mutations in EHMT1 cause the 9q34 subtelomeric deletion syndrome, 2006. Rots D. et al. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes. American Journal of Human Genetics, 2024. Hnízda A. et al. De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity. Nature Communications, 2026.