• Duncan Astle

A single-gene disorder affects brain organisation

Many children struggle with learning particular skills despite good access to learning opportunities. For instance, some children need more time and considerably more effort to learn language compared to their peers. In some cases, this is associated with other problems, e.g. in certain types of childhood epilepsy, in others, these difficulties occur in isolation, e.g. specific language impairment. It is vital to understand the processes that lead to these difficulties so that problems can be identified early and treated with the most effective interventions. Yet, understanding these developmental difficulties still poses a scientific challenge. We know that genetic predisposition plays a role based on heritability studies and intermediate difficulties in family members. However, learning difficulties are associated with a large number of genes that individually have only very small effects. A possible reason for this could be that developmental disorders that are defined on the basis of behaviour reflect a mixture of underlying biology. This heterogeneity makes it very difficult to establish any causative mechanism.

One way of getting around this conundrum is to study known genetic disorders that share some similarity with more common developmental syndromes. To this end, we investigated a case group of individuals with mutations in a particular gene. We established that this mutation is associated with disproportionate deficits in attention, language, and oro-motor control (Baker et al., 2015). In the current study, we explored the effect of this genetic mutation on the organisation of the brain network to understand how a genetic difference may lead to differences in thinking and behaviour. Brain regions with typically high expression of this gene showed the highest connectivity, which may indicate that it is important for the development of structural connections. Further, cases with mutations in this gene displayed reduced efficiency of information transfer in the brain network. These findings suggest that brain organisation may provide an important intermediate level of description that could help to reveal how genetic differences give rise to learning difficulties. We hope to extend this work to compare brain organisation between genetic groups and developmental disorders directly in the future.

The article about the study is now available as a preprint:  http://dx.doi.org/10.1101/057687

Interested readers can also retrieve the analysis scripts for this study here:  https://github.com/joebathelt/ZDHHC9_connectome

Reference:

Baker, K., Astle, D. E., Scerif, G., Barnes, J., Smith, J., Moffat, G., et al. (2015). Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations. Annals of Clinical and Translational Neurology, n/a–n/a. http://doi.org/10.1002/acn3.196

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