Research Notes

Ho Ming Chow1 and Soo-Eun Chang2
1
Communication Sciences and Disorders Program, University of Delaware, Newark, DE 
2Department of Psychiatry, University of Michigan, Ann Arbor, MI

Stuttering is widely considered as a neurodevelopmental disorder, an umbrella term comprising childhood-onset disorders that affect the development of specific abilities, including executive control, language, and motor function, with no obvious cause. Like many neurodevelopmental disorders, the etiology of stuttering is not fully known and is likely to be complex. 

Heritability of stuttering is relatively high but there is no clear pattern of inheritance, indicating a multifactorial/polygenetic etiology (Kraft and Yairi, 2012; Frigerio-Domingues and Drayna, 2017).  Although the etiology of stuttering is not fully understood, accumulating results from neuroimaging research show that atypical function and structure, and connectivity among brain regions that support speech-motor control exist in both children and adults who stutter (for a review, see (Neef et al., 2015; Chang et al., 2018). To date, genetics and brain imaging research in the field of stuttering have largely been conducted in parallel, with little if any cross-discipline collaborations. On one hand, genetics research can reveal potential gene mutations associated with stuttering, providing critical insights into possible molecular and cellular bases of stuttering. It is difficult, however, to reconcile how basic cell functions such as lysosomal enzyme trafficking – a biological pathway associated with the recent discovery of stuttering related genes reported by Drayna and colleagues – relate to the complex speech control abilities that are affected in stuttering. How can we connect the many dots between basic cell function and stuttering? Here, neuroimaging could serve as a bridge between genetics and the behavior of interest (speech). That is, measures extracted via neuroimaging (e.g., functional and structural MRI measures that differentiate people who stutter from those who don’t) can serve as an “intermediate phenotype” that is expressed through genetic variation. 

When a gene is expressed (sometimes referred to as a gene being “turned on”), that means the functional product encoded by the gene is synthesized. We can posit that if a gene is highly expressed in certain areas of the brain, mutation of that gene can have a higher effect in that brain area, and vice versa. Therefore, examining the pattern of normal expression level of a gene across brain areas provide opportunities to predict the genetic effect on specific regions of the brain. This approach was used in previous studies that showed that expression patterns of risk genes obtained from donor samples are associated with MRI abnormalities in several neurological disorders (Romme et al., 2017; McColgan et al., 2018).

Using this novel approach to link brain imaging measures and gene expression, we conducted two recent studies where we used gene expression data available through the Allen Institute of Brain Science, which maps the expression patterns of all ~20,000 protein coding genes of six human donors’ genome onto a brain template (Hawrylycz et al., 2012). We used these maps to compare the spatial expression patterns of the genes discovered by Drayna and colleagues to be associated with stuttering (Kang et al., 2010; Raza et al., 2015), to the differences between children who stutter and non-stuttering peers in terms of functional connectivity patterns (Benito-Aragón et al., 2019) and gray matter volume (Chow et al., 2019). We found that both patterns of functional and structural differences were highly correlated with the expression pattern of one of the previously identified stuttering genes, GNTPG. Furthermore, we found that the pattern of structural differences was also correlated with a disproportionately large number of genes associated with energy metabolism. These results provide first glimpses into how basic gene functions, i.e., intercellular trafficking and metabolic functions, might affect brain function in stuttering. The results from these two recent studies seem to suggest that alteration of these basic cellular functions, which may be exacerbated during early development (e.g., 2-3 years) when there is a surge of metabolic demands in the brain, could lead to the changes in brain anatomy and function associated with vulnerability for developing stuttering. Much more research needs to be done to confirm and expand the findings, but these new reports pave the way in providing new insights into the biological bases of stuttering.

Benito-Aragón, C., Gonzalez-SarmientoR., Liddell, T., Diez, I., d'Oleire Uquillas, F., Ortiz-Terán, L., Bueichekú, E., Chow, H., Chang, S-E., Sepulcre, J. (2019).  Lysosomal and Neurofilament Genes Define the Cortical Network of Stuttering. Progress in Neurobiology. doi: 10.1016/j.pneurobio.2019.101718 .https://www.sciencedirect.com/science/article/pii/S0301008219303363?via%3Dihub

Chang, S-E., Garnett, E.O, Etchell, A.C., Chow, H (2018). Functional and Neuroanatomical Bases of Developmental Stuttering: Current Insights. (2018). Neuroscientist. Epub September 28, 2018. https://doi.org/10.1177/1073858418803594 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486457/

Chow, H., Garnett, E.O., Li, H., Etchell, A., Sepulcre, J., Drayna, D., Chugani, D., Chang, S-E. (2019). Linking lysosomal enzyme targeting genes and energy metabolism with altered gray matter volume in children with persistent stuttering. bioRxiv 848796; doi: https://doi.org/10.1101/848796

Frigerio-Domingues C, Drayna D. Genetic contributions to stuttering: the current evidence. Mol Genet Genomic Med 2017; 5: 95–102. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370225/

Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012; 489: 391–399. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243026/

Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, et al. Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering. N Engl J Med 2010; 362: 677–685. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936507/

Kraft SJ, Yairi E. Genetic bases of stuttering: the state of the art, 2011. Folia Phoniatr Logop Off Organ Int Assoc Logop Phoniatr IALP 2012; 64: 34–47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696365/

McColgan P, Gregory S, Seunarine KK, Razi A, Papoutsi M, Johnson E, et al. Brain Regions Showing White Matter Loss in Huntington’s Disease Are Enriched for Synaptic and Metabolic Genes. Biol Psychiatry 2018; 83: 456–465. https://www.ncbi.nlm.nih.gov/pubmed/29174593

Neef NE, Anwander A, Friederici AD. The Neurobiological Grounding of Persistent Stuttering: from Structure to Function [Internet]. Curr Neurol Neurosci Rep 2015; 15[cited 2018 Oct 26] Available from: 

https://www.researchgate.net/publication/280582565_The_Neurobiological_Grounding_of_Persistent_Stuttering_from_Structure_to_Function

Raza MH, Mattera R, Morell R, Sainz E, Rahn R, Gutierrez J, et al. Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering. Am J Hum Genet 2015; 97: 715–725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667129/

Romme IAC, de Reus MA, Ophoff RA, Kahn RS, van den Heuvel MP. Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia. Biol Psychiatry 2017; 81: 495–502. https://www.biologicalpsychiatryjournal.com/article/S0006-3223(16)32618-X/fulltext