Severe speech disorders in rare genetic diseases: a brain imaging investigation

Background:
Speech is a uniquely human skills critical to children’s social and emotional development. Oral language skills are also crucial to their later academic attainments. In several rare diseases of genetic origin, children fail to develop speech appropriately however, and remain minimally verbal or hardly intelligible throughout their lifespan. Sometimes this severe speech disorder is part of a known genetic syndrome, but in other cases a causal link has not yet been identified. No treatments seem effective, partly due to the lack of knowledge about the biological basis of such disorders [1]. In many cases, brain MRIs do not show macroscopic anomalies.

Our team has previously identified grey and white matter differences (”neural phenotypes”) in children as well as in families with inherited speech conditions linked to FOXP2 [2], GRIN2A (in preparation), and unidentified variants [3,4]. At UCL and via a collaboration with MCRI (Australia: https://www.ucl.ac.uk/child-health/centre-research-excellence-speech-and-language), we have collected further MRI and phenotypic data from individuals with other rare conditions where speech is the main challenge (such as NF1).

This project aims to identify the relationship between speech-language phenotypes and neural phenotypes. We think that identifying specific brain networks affected will accelerate translation and help develop personalized treatments.

Aims/Objectives:
To characterize the brain differences within and across rare genetic conditions that severely affect speech development.

Methods:
This project will combine a retrospective and prospective approach: (i) analysis of MRI data already available (~30) and (ii) data collection of MRI and phenotypic characterization of new patients with unidentified or rare variants (to be updated as new genes are discovered [5]).

Phenotyping will involve a battery of assessments across intelligence, language, executive functions, speech and literacy. Some can be done remotely.

Neuroimaging analysis will examine white matter using tractography as well as cortical morphometry and subcortical volumes, as in our previous publications. Novel relevant methods examining networks will also be explored.

Timeline:
Year 1: Review of the literature; training on data analysis pipelines; analysis of existing datasets; setting up of prospective study.
Year 2: analysis of existing datasets; article writing; data collection of prospective cases.
Year 3: Comparison across genotypes; article writing and dissemination; writing up of thesis.

References:
1. Morgan, A.T., Bonthrone, A., Liégeois, F. (2016) Brain basis of childhood speech and language disorders: are we closer to clinically meaningful MRI markers? Current Opinions in Pediatrics, 28(6), 725-730.
2. Liégeois, F., Hildebrand, M., Bonthrone, A., Turner, S.J., Scheffer, I.E., Bahlo, M., Connelly, A., Morgan, A.T. (2016) Early neuroimaging markers of FOXP2 intragenic deletion Scientific Reports, 6, Article number: 35192.
3. Liégeois, F., Turner, S., Mayes, A., Bonthrone, A.,Boys, A., Parry-Fielder, B., Spencer-Smith, M., Bahlo, M., Scerri, T., Hildebrand, M., Scheffer, I., Connelly, A., Morgan, A. (2019). Dorsal language stream anomalies in an inherited speech disorder. Brain, 142 (4), 966–977. DOI: 10.1093/brain/awz018.
4. Morgan, A.T., Su, M., Reilly, S., Conti-Ramsden, G., Connelly, A., Liégeois, F. (2018) A brain marker for developmental speech disorder. Journal of Pediatrics, 198, 234-239.
5. Morgan, A., Braden, R., Wong, M., Colin, E., Amor, D., Liegeois, F., Srivastava, S., Vogel, A., Bizaoui, V., Ranguin, K., Fisher, S., van Bon, B (In Press). Speech and language deficits are central to SETBP1 haploinsufficiency disorder. European Journal of Human Genetics.