Nandakumar, R.; Shi, X.; Gu, H.; Kim, Y.; Raskind, W.; Peter, B.; Dinu, V.

Dyslexia is a learning disability that negatively affects reading, writing, and spelling development at the word level in 5%-9% of children. The phenotype is variable and complex, involving several potential cognitive and physical concomitants such as sensory dysregulation and immunodeficiencies. The biological pathogenesis is not well-understood. Toward a better understanding of the biological drivers of dyslexia, we conducted the first joint exome and metabolome investigation in a pilot sample of 30 participants with dyslexia and 13 controls. In this analysis, eight metabolites of interest emerged (pyridoxine, kynurenic acid, citraconic acid, phosphocreatine, hippuric acid, xylitol, 2-deoxyuridine, and acetylcysteine). A metabolite-metabolite interaction analysis identified Krebs cycle intermediates that may be implicated in the development of dyslexia. Gene ontology analysis based on exome variants resulted in several pathways of interest, including the sensory perception of smell (olfactory) and immune system-related responses. In the joint exome and metabolite analysis, the olfactory transduction pathway emerged as the primary pathway of interest. Although the olfactory transduction and Krebs cycle pathways have not previously been described in dyslexia literature, these pathways have been implicated in other neurodevelopmental disorders including autism spectrum disorder and obsessive-compulsive disorder, suggesting the possibility of these pathways playing a role in dyslexia as well. Immune system response pathways, on the other hand, have been implicated in both dyslexia and other neurodevelopmental disorders.