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Accessibility Statement

Utilizing an in vivo model to decipher the molecular disease mechanism in CHD4-related neurodevelopmental disorder

Sifrim-Hitz-Weiss syndrome is a rare neurodevelopmental disorder caused by mutations in CHD4 encoding a chromatin remodeler involved in transcriptional regulation and embryonic development. The majority of damaging mutations are heterozygous missense substitutions that arise de novo in patients. Currently, the molecular mechanism is unknown, but a dominant negative effect is suspected as most patients have missense variants and truncating variants were observed in healthy individuals. Furthermore, there are differences in the properties of different pathogenic missense substitutions and genotype-phenotype correlations.  This phenomenon of mainly missense substitutions is seen in other Mendelian neuro-developmental disorders and complicates clinical diagnostics and variant interpretation. Understanding the molecular disease mechanism, haploinsufficiency versus dominant-negative will aid in clinical variant classification. It is also crucial for development of future gene therapies for the CHD4 related disorder and similar disorders. In this study we aim to create an in-vivo system, using Xenopus that will provide insights on the early role of CHD protein on brain development and enable a systematic evaluation of various mutations observed in patients. 

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