Developmental Dyslexia: Insights from EEG-Based Findings and Molecular Signatures-A Pilot Study

Abstract

Developmental dyslexia (DD) is a learning disorder. Although risk genes have been identified, environmental factors, and particularly stress arising from constant difficulties, have been associated with the occurrence of DD by affecting brain plasticity and function, especially during critical neurodevelopmental stages. In this work, electroencephalogram (EEG) findings were coupled with the genetic and epigenetic molecular signatures of individuals with DD and matched controls. Specifically, we investigated the genetic and epigenetic correlates of key stress-associated genes (NR3C1, NR3C2, FKBP5, GILZ, SLC6A4) with psychological characteristics (depression, anxiety, and stress) often included in DD diagnostic criteria, as well as with brain EEG findings. We paired the observed brain rhythms with the expression levels of stress-related genes, investigated the epigenetic profile of the stress regulator glucocorticoid receptor (GR) and correlated such indices with demographic findings. This study presents a new interdisciplinary approach and findings that support the idea that stress, attributed to the demands of the school environment, may act as a contributing factor in the occurrence of the DD phenotype.

Keywords: HPA axis genes; developmental dyslexia; electroencephalogram; stress.

Figure 1

mRNA levels of stress-associated genes of interest as well as methylation status of regions 1_D and 1_F in the NR3C1 gene promoter. (A) Examination of mRNA levels NR3C1 NR3C2, GILZ and FKBP5, DD samples vs. control samples. (B) (i) Schematic representation of the CpG island of NR3C1 gene with individual sites for 1_D and 1_F alternative untranslated first exons. (ii) Methylation percentages of the 1_D CpG and (iii) 1_F CpG sites. Asterisk (*) indicates a p-value < 0.05 and a double asterisk (**) indicates a p-value < 0.01. Abbreviations: GR, glucocorticoid receptor; MR, mineralocorticoid receptor; GILZ, glucocorticoid-induced leucine zipper.

Figure 2

Gene interaction network of dyslexia and stress-associated genes. Target genesare shown in the inner circle, while genes associated with the query genes are shown in the outer one. The left panel presents the different types of interactions with respective color coding, depicted with lines connecting genes in the network: physical interactions (pink), predicted (orange), co-expression (purple), genetic interaction (green) and shared protein domains (yellow). The right panel presents gene functions, represented with colored strips within the respective genes: hormone-mediated signaling pathway (red), cellular response to steroid hormone stimulus (green) and steroid hormone-mediated signaling pathway (blue), cilium assembly (orange) and response to steroid hormone (purple).