About 1 in 650-1000 children are born with a 47,XXY, 47,XXX or 47,XYY chromosomal pattern (i.e, sex chromosome trisomies, SCT). The presence of SCT is associated with an increased risk for... Show moreAbout 1 in 650-1000 children are born with a 47,XXY, 47,XXX or 47,XYY chromosomal pattern (i.e, sex chromosome trisomies, SCT). The presence of SCT is associated with an increased risk for neurodevelopmental difficulties across the life-span. Studying neurodevelopment in early childhood in children with SCT could signal deviations in development that serve as risk markers to guide clinical care. This thesis explored the development of self-regulation (emotion, cognition, and behavior) in SCT children and population-based controls, aged 1 to 7 years, who participated in the TRIXY Early Childhood Study. Behavioral symptoms were assessed through structured behavioral observation and parental questionnaires. Neurocognition was measured using performance tests and psychophysiological measures of arousal. Outcomes showed behavioral symptoms of psychopathology and neurocognitive vulnerabilities, already from an early age. Difficulties in self-regulation tended to become more pronounced with increasing age and were rather robust; independent of karyotype, pre/postnatal diagnosis, or intelligence-levels. A developmental neurocognitive perspective is key in increasing our knowledge of gene-brain-behavior pathways in SCT as well as advancing clinical care (diagnostics and treatment). Self-regulation amongst other neurocognitive functions may serve as a valuable target for early, tailor-made interventions to minimize the risk for psychopathology later in life and improving quality of life. Show less
Boer, E. de; Ockeloen, C.W.; Kampen, R.A.; Hampstead, J.E.; Dingemans, A.J.M.; Rots, D.; ... ; Kleefstra, T. 2022
Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We... Show morePurpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. Show less
