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Den Hoed, J. (2022). Disentangling the molecular landscape of genetic variation of neurodevelopmental and speech disorders. PhD Thesis, Radboud University Nijmegen, Nijmegen.
Additional information
full text via Radboud Repository -
Van der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I. and 26 moreVan der Spek, J., Den Hoed, J., Snijders Blok, L., Dingemans, A. J. M., Schijven, D., Nellaker, C., Venselaar, H., Astuti, G. D. N., Barakat, T. S., Bebin, E. M., Beck-Wödl, S., Beunders, G., Brown, N. J., Brunet, T., Brunner, H. G., Campeau, P. M., Čuturilo, G., Gilissen, C., Haack, T. B., Hüning, I., Husain, R. A., Kamien, B., Lim, S. C., Lovrecic, L., Magg, J., Maver, A., Miranda, V., Monteil, D. C., Ockeloen, C. W., Pais, L. S., Plaiasu, V., Raiti, L., Richmond, C., Rieß, A., Schwaibold, E. M. C., Simon, M. E. H., Spranger, S., Tan, T. Y., Thompson, M. L., De Vries, B. B., Wilkins, E. J., Willemsen, M. H., Francks, C., Vissers, L. E. L. M., Fisher, S. E., & Kleefstra, T. (2022). Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome. Genetics in Medicine, 24(6), 1283-1296. doi:10.1016/j.gim.2022.02.014.
Abstract
Purpose
Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.
Methods
We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.
Results
Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.
Conclusion
Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease. -
Castroflorio, E., Den Hoed, J., Svistunova, D., Finelli, M. J., Cebrian-Serrano, A., Corrochano, S., Bassett, A. R., Davies, B., & Oliver, P. L. (2020). The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour. Cellular and Molecular Life Sciences. doi:10.1007/s00018-020-03721-6.
Abstract
Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. -
Den Hoed, J., & Fisher, S. E. (2020). Genetic pathways involved in human speech disorders. Current Opinion in Genetics & Development, 65, 103-111. doi:10.1016/j.gde.2020.05.012.
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