314 research outputs found
Exploring Kleefstra syndrome cohort phenotype characteristics:Prevalence insights from caregiver-reported outcomes
No full textKleefstra syndrome (KLEFS1) is a rare genetic neurodevelopmental disorder affecting multiple body systems. It continues to be under-researched, and its prevalence remains unknown. This paper builds on the international KLEFS1 cohort of 172 individuals based on the caregiver-reported outcomes collected within the online data collection platform GenIDA and reports the occurrence, frequency and severity of symptoms in KLEFS1. The study clearly shows the importance of caregiver-reported outcomes collections in the rare disease domain. Moreover, the study emphasizes the need for more specific and enhanced data collection methods, suggesting recommendations to optimize caregiver-reported registries and foster an even more profound understanding of rare diseases.</p
Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals
No full textOBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life
Parental experiences and needs in Kleefstra Syndrome:A semi-structured interview study
No full textKleefstra Syndrome (KLEFS1) is a monogenic neurodevelopmental disorder characterized by developmental delays, somatic issues, and (neuro)psychiatric symptoms. Individuals with KLEFS1 often require complex, ongoing support, which significantly impacts family life. To effectively improve care and support for families, a better understanding is needed of the impacts of raising a child with KLEFS1 on the family and families' support needs. We conducted a semi-structured interview study among parents of children with KLEFS1 to investigate these impacts. The interviews were audio-recorded, transcribed, coded, and thematically analyzed. We conducted 12 interviews with 15 parents of children with KLEFS1 (8–25 years old), in the Netherlands and Belgium. Over the years, parents have encountered significant challenges. Although parents value timely diagnosis, the emotional impact was profound, especially for parents of younger children. Parents focused on their children's developmental symptoms, and behavioral and psychiatric symptoms, which had significant impacts, including impacts on parents' employment status, their ability to undertake activities, and emotional well-being. Parents were concerned about their children's future, because of children's lifelong dependency and risk of regression. Parents prioritized receiving adequate care and support to decrease the burden on their family and to improve their child's well-being. To better support families, the accessibility of social support needs to be improved, e.g., by expanding respite care services and specialized schooling, simplifying regulations for accessing social support, and providing tailored emotional support and information during the diagnostic process. When developing treatments, researchers should incorporate parental experiences in defining patient-relevant outcome measures.</p
Expanding the phenotype of Kleefstra syndrome:speech, language and cognition in 103 individuals
No full textObjectives Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome.Method 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained.Results The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression.Conclusions The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life
Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome
No full textContains fulltext :
95713.pdf (Publisher’s version ) (Open Access)The core phenotype of Kleefstra syndrome (KS) is characterized by intellectual disability, childhood hypotonia, and a characteristic facial appearance. This can be caused by either submicroscopic 9q34 deletions or loss of function mutations of the EHMT1 gene. Remarkably, in three patients with a clinical suspicion of KS, molecular cytogenetic analysis revealed an interstitial 9q34 microdeletion proximal to the coding region of the EHMT1 gene based on the NM_ 024757.3 transcript. Because we found a mono-allelic EHMT1 transcript suggestive for haploinsufficiency of EHMT1 in two of these patients tested, we hypothesized that a deletion of regulatory elements or so far unknown coding sequences in the 5' region of the EHMT1 gene, might result in a phenotype compatible with KS. We further characterized the molecular content of deletions proximal to the transcript NM_ 024757.3 and confirmed presence of a novel predicted open reading frame comprising 27 coding exons (NM_ 024757.4). Further analysis showed that all three deletions included the presumed novel first exon of the EHMT1 gene. Subsequent testing of 75 individuals without previously detectable EHMT1 aberrations showed one additional case with a deletion comprising only this 5' part of the gene. These results have important implications for the genetic screening of KS and for studies of the functional significance of EHMT1
Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome
No full textKleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease
Sleep disturbance as a precursor of severe regression in Kleefstra syndrome suggests a need for firm and rapid pharmacological treatment
No full textIntellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning
Chromatin Architecture Shapes the Immune System : Chromatinopathies Perspective
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Growth, body composition, and endocrine-metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies
No full textMendelian neurodevelopmental disorders caused by variants in genes encoding chromatin modification can be categorized as Mendelian disorders of the epigenetic machinery (MDEMs). These disorders have significant overlap in molecular pathways and phenotypes including intellectual disability, short stature, and obesity. Among the MDEMs is Kleefstra syndrome (KLFS), which is caused by haploinsufficiency of EHMT1. Preclinical studies have identified metabolic dysregulation and obesity in KLFS models, but proper clinical translation lacks. In this study, we aim to delineate growth, body composition, and endocrine-metabolic characteristics in a total of 62 individuals with KLFS. Our results revealed a high prevalence of childhood-onset overweight/obesity (60%; 28/47) with disproportionately high body fat percentage, which aligns perfectly with previous preclinical studies. Short stature was common (33%), likely due to advanced skeletal maturation. Endocrine-metabolic investigations showed thyroid dysregulation (22%; 9/41), elevated triglycerides, and decreased blood ammonia levels. Moreover, hand radiographs identified decreased bone mineralization (57%; 8/14) and negative ulnar variance (71%; 10/14). Our findings indicate a high (cardio)metabolic risk in KLFS. Therefore, we recommend monitoring of weight and endocrine-metabolic profile. Supporting a healthy lifestyle and screening of bone mineralization is advised. Our comprehensive results support translational research and contribute to a better understanding of MDEM-associated phenotypes
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