The DCDC2/intron 2 deletion and white matter disorganization: Focus on developmental dyslexia

Abstract

Introduction The DCDC2 gene is involved in neuronal migration. Heterotopias have been found within the white matter of DCDC2-knockdown rats. A deletion in DCDC2/intron 2 (DCDC2d), which encompasses a regulatory region named ‘regulatory element associated with dyslexia 1’ (READ1), increases the risk for dyslexia. We hypothesized that DCDC2d can be associated to alterations of the white matter structure in general and in dyslexic brains. Methods Based on a full-factorial analysis of covariance (ANCOVA) model, we investigated voxel-based diffusion tensor imaging (VB-DTI) data of four groups of subjects: dyslexia with/without DCDC2d, and normal readers with/without DCDC2d. We also tested DCDC2d effects upon correlation patterns between fractional anisotropy (FA) and reading scores. Results We found that FA was reduced in the left arcuate fasciculus and splenium of the corpus callosum in subjects with versus without DCDC2d, irrespective of dyslexia. Subjects with dyslexia and DCDC2d showed reduced FA, mainly in the left hemisphere and in the corpus callosum; their counterpart without DCDC2d showed similar FA alterations. Noteworthy, a conjunction analysis in impaired readers revealed common regions with lower FA mainly in the left hemisphere. When we compared subjects with dyslexia with versus without DCDC2d, we found lower FA in the inferior longitudinal fasciculus and genu of the corpus callosum, bilaterally. Normal readers with versus without DCDC2d had FA increases and decreases in both the right and left hemisphere. Discussion The major contribution of our study was to provide evidence relating genes, brain and behaviour. Overall, our findings support the hypothesis that DCDC2d is associated with altered FA. In normal readers, DCDC2-related anatomical patterns may mark some developmental cognitive vulnerability to learning disabilities. In subjects with dyslexia, DCDC2d accounted for both common – mainly located in the left hemisphere – and unique – a more severe and extended pattern – alterations of white matter fibre tracts.

Neural Noise Hypothesis of Developmental Dyslexia

“…For example, one study [37] provides evidence that poor access to phonological representations, arguably reflected in reduced functional connectivity with temporoparietal regions, is impaired, while phonological representations remain intact, although this study did not examine the detailed properties of phoneme encoding (as has been done in other studies [87]). RD risk mutations in DCDC2 have also been linked to structural connectivity within the reading network [25] and children at risk for RD have persistently reduced temporoparietal white matter integrity [99]. While these studies highlight the importance of connectivity in RD and the need for systems-levels approaches to studying RD, these results are not necessarily incompatible with the neural noise hypothesis.…”

“…In addition, there is evidence that the interference technique used to produce knockdown phenotypes (used by Centanni et al [3,10]) can have phenotypic effects unrelated to the target gene [69,70]. Finally, we note that these genes have also been associated with neurobiological phenotypes other than those discussed, such as corpus callosum area in rats (Kiaa0319 [13]) and white matter integrity in humans in both corpus callosum and left arcuate fasciculus (DCDC2 [25]). …”

“…An increasing number of studies have investigated the function of RD risk genes in animal models [2][3][4][5][6][7][8][9][10][11][12][13], and the neurobiological and behavioral consequences of genetic RD risk variants in humans [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], motivating the need for a synthesis of these findings, especially because they relate to emerging avenues of human research on the role of neurochemistry [32] and neural oscillations [33][34][35][36] in RD. Here, we present a timely integration of diverse lines of current research linking some of the key neural and behavioral deficits associated with RD to basic neural processes.…”

Predicting Developmental Dyslexia: A Brief Review of Genetics, Language and the Brain

“…Cortical ectopias have previously been shown in postmortem studies of adults with DD [19]. Furthermore, DCDC2 deletion in humans with DD has been linked to reduced fractional anisotropy (FA), a measure of fiber tract integrity, in the left arcuate fasciculus and the genu of the corpus callosum [20]. This is consistent with the notion that some factors causing DD are present prior to learning to read and possibly at birth.…”

Dissociations among linguistic, cognitive, and auditory-motor neuroanatomical domains in children who stutter

“…A recent study found that relative to CWNS, CWS show reduced FA in white matter tracts connecting auditory and motor regions, corpus callosum, and tracts connecting cortical and subcortical regions; specifically, these included the left SLF, left IFG, left (pre)motor regions, and left pSTG/middle temporal gyrus (Chang, Zhu, Choo, & Angstadt, 2015). Similar to dyslexia (Marino et al, 2014), CWS showed lower FA values primarily in the left hemisphere. Although attenuated FA values in CWS were also observed in the right hemisphere, group differences here were much smaller than that found in the left hemisphere.…”