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Objectives 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. [ABSTRACT FROM AUTHOR]

Aims Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. Methods and results Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17–25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. Conclusion In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease. [ABSTRACT FROM AUTHOR]

Objective: Several instruments are available for measuring (aspects of) adaptive functioning, but knowledge is lacking about which is best to use to monitor patients with etiologically homogeneous neurodevelopmental disorders. In this study we compare the use of the Vineland-Z and ABAS-3 adaptive behavior scales in such a specific group. Method: Of patients with a molecularly confirmed diagnosis of Kleefstra syndrome, 34 were assessed with both the Vineland-Z and ABAS-3 of which 12 (35,3%) males and 22 (64,7%) females. Raw scores and developmental ages were calculated and a comparison between the instruments was done via correlation analysis. Results: Biological age ranged from 12 to 50 years old (median age of 23,1 ± 9,6 years). Pearson r correlation analyses show that the Vineland-Z and ABAS-3 assessments are highly interchangeable in this population. However, there are practical issues which require attention: (i) the use of ABAS-3 needs several versions to cover the whole adaptive spectrum, and (ii) the Vineland-Z discriminates more at the lower end of the adaptive functioning spectrum compared to the ABAS-3, but less at the higher end. An ideal instrument for this specific purpose is not yet available. Conclusions: We recommend that either the Vineland-Z, with modification of the dated items, the abridged version of the Vineland III, or a merge of the 0-4/5-17 ABAS-3 versions would work best to assess the entire spectrum of adaptive functioning adequately. [ABSTRACT FROM AUTHOR]

Mendelian 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., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)