To provide the molecular characterizations and clinical profiles in patients with KLEFS1(Kleefstra syndrome 1) of Chinese ethic group and explore the genotype-phenotype correlation in this underrepresented population. A total of 35 Mainland Chinese patients with KLEFS1 were reported in the present study. The clinical data were assessed through reviewing medical records and standardized medical history questionnaires. We analyzed EHMT1 variants and 9q34.3 microdeletion and performed genotype–phenotype correlation in two groups. 17 novel variants of EHMT1 were identified, adding to the genetic landscape of the disorder. For the first time, we retrospectively describe the prenatal presentations and assess facial dysmorphisms in our cohort. There was no significant difference between the two groups in prevalence of clinical manifestations such as DD/ID, neurological symptoms, behavioral issues, obesity, congenital cardiac anomalies, male genital anomalies, or most other related clinical features, including developmental quotients (DQ). However, the frequencies of everted lower lip, small and spaced teeth, short neck, and renal anomalies were significantly higher among patients with deletions encompassing more than EHMT1 compared to those with EHMT1 variants (or deletions only disrupting EHMT1), with rates of 20% vs. 83.3% (P = 0.014), 14.3% vs. 80%(P = 0.017)13.3% vs. 66.7% (P = 0.031) and 5.3% vs. 42.9% (P = 0.047) respectively. This is the largest series of patients with KLEFS1 published to date in Mainland China. EHMT1 haploinsufficiency contributes to the majority of important phenotypes of KLEFS1. Our findings enrich our knowledge of 9q34.3 microdeletion and enhance our comprehension of the pathogenic molecular mechanisms of EHMT1. The online version contains supplementary material available at 10.1186/s13023-025-04076-6.

Kleefstra syndrome is a rare genetic disorder attributed to loss of function of EHMT1, either due to a point mutation or a microdeletion in the chromosome region 9q34.3. This gene encodes an enzyme that modifies histone function and is essential for normal development. Individuals with Kleefstra syndrome typically present intellectual disability (from moderate to severe), language delay, autism spectrum disorders, generalized hypotonia, and distinctive facial dysmorphic features. Additional manifestations in children may include cardiac defects, renal and urological malformations, genital anomalies, respiratory infections, epilepsy (including febrile seizures), and psychiatric disorders. Panayiotopoulos syndrome is a specific type of epilepsy, usually presenting in early to mid-childhood with benign focal seizures. These seizures are characterized by primarily autonomic symptoms, abnormal EEG findings showing shifts or multiple seizure foci (often located in occipital lobe), and other autonomic manifestations such as pallor, redness or cyanosis, mydriasis or miosis, heart and breathing problems, thermoregulatory changes, urinary and/or fecal incontinence, hypersalivation, and altered gut motility. We present the case of a child with Kleefstra syndrome and Panayiotopoulos epilepsy. The patient is a 12-year-old male born from a full-term pregnancy to non-consanguineous healthy parents with a family history of neurodevelopmental disorders. At birth, he presented dysmorphic facial features including receding forehead, low-set ears and lingual protrusion. From 6 months of age, he manifested predominantly axial and lower limb hypotonia, associated with a delay in acquiring psychomotor developmental milestones. Genetic counseling was requested, and array-CGH was then performed. Molecular analysis detected a 9q34.3 microdeletion which included the EHMT1 gene, leading to Kleefstra syndrome diagnosis. From the age of 6 years, he began experiencing seizures with features typical of Panayiotopoulos epilepsy and started treatment with valproic acid. We highlight the association between Panayiotopoulos epilepsy and Kleefstra syndrome, which has not been previously reported in the literature. Although this kind of epilepsy is quite frequent in pediatric age and the possibility of a casual co-occurrence should be considered, however in Kleefstra syndrome patients carrying 9q34.3 microdeletion a potential additional role of genetic (besides EHMT1) and epigenetic factors in developing seizures cannot be excluded. The present data expand the genomic and phenotypical features of the syndrome, providing new insights about research, which are useful to achieve genotype/phenotype correlations and better management of affected subjects.

Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes.

Kleefstra syndrome (KLEFS1) is a rare genetic disorder primarily caused by the deletion of the chromosome 9q34.3 genomic segment or pathogenic mutations in the euchromatin histone methyltransferase 1 (EHMT1) gene. It is characterized by intellectual disability or impairment, childhood hypotonia, and distinct facial features. Notably, cardiovascular defects especially congenital heart diseases also represent a major feature of KLEFS1. While the neuropsychiatric aspects of KLEFS1 have been extensively documented and researched, the cardiovascular manifestations have not received adequate attention. The majority of KLEFS1 patients often present with a spectrum of cardiovascular defects, including abnormal cardiac structure, arrhythmias, valve abnormalities, cardiomyopathy, and coronary artery abnormalities. Here, we systematically searched and reviewed previously published articles and case reports related to KLEFS1, conducting a comprehensive analysis of the existing literature to highlight the cardiovascular manifestations of this genetic disorder and explore the potential correlations between the cardiac phenotype and KLEFS1. Clinical trial number: Not applicable.

Kleefstra Syndrome (KS) is a rare genetic neurodevelopmental disorder caused by a microdeletion in chromosomal region 9q34.3 or a mutation in the euchromatin histone methyltransferase 1 (EHTM1) gene. Patients with KS show a range of clinical symptoms, including delay in motor and speech development, intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial dysmorphic features. The patient is a four-year-old girl who was initially diagnosed with developmental motor delay by a pediatric neurologist and referred to an occupational therapy clinic at the age of six months. The initial assessment showed hypotonia and difficulties with rolling. Occupational therapy intervention was based on principles of neurodevelopmental treatment and sensory integration (SI) with cognitive integration and activities of daily living (ADL) training. With continuous occupational therapy services over more than three years, she overcame many disabilities and improved in occupational performance skills such as gross and fine motor skills as well as cognitive abilities, although her verbal communication skills were not effective. The patient's progress was as follows: she began rolling over at seven months, achieved independent sitting at ten months, crawled at eighteen months, stood with support at twenty months, and took her first steps at twenty-six months. The predominant problem was speech delay, which was noticeable in this syndrome. When a patient is being referred because of KS, occupational and speech therapy assessments should be accurately implemented.