Growth, body composition, and endocrine‐metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies

Abstract

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.

Establishment of Human Pluripotent Stem Cell-derived Cortical Neurosphere Model to Study Pathomechanisms and Drug Sensitivity in Kleefstra Syndrome

“…In addition, G9a/GLP (the corresponding protein products of EHMT2/EHMT1) inhibition induced change in morphology in cell lines accompanied by the appearance of smaller neurosphere-like cells in SH-SY5Y neuroblastoma cultures 36 . Whether these cellular defects contribute or not to microcephaly seen in more than 55% of the KS-patients 37 is not clear and needs further investigation. Our results together with the cited references demonstrate that EHMT1 has a universal role in basic cellular mechanisms like cell cycle regulation, cell proliferation, survival, and migration regardless of cell type.…”