Genetic research into dyslexia

The genetic research into dyslexia has its roots in the work of Galaburda and Kemper, 1979,^[1] and Galaburda et al. 1985,^[2] from the examination of post-autopsy brains of people with dyslexia. When they observed anatomical differences in the language center in a dyslexic brain, they showed microscopic cortical malformations known as ectopias and more rarely vascular micro-malformations, and in some instances these cortical malformations appeared as a microgyrus. These studies and those of Cohen et al. 1989^[3] suggested abnormal cortical development which was presumed to occur before or during the sixth month of foetal brain development.^[4]

Overview

High genetic concordance found in twin studies suggest a significant genetic influence on reading ability,^[5][6] although the degree depends on the definition of dyslexia.^[7] Linkage analysis and genetic association studies (typically quantitative trait locus association studies, which use microarrays to look at single nucleotide polymorphisms of multiple genes at once) have been used to identify candidate genes that may be implicated in dyslexia.^[8] Several genes have been linked to dyslexia, including DCDC2^[9][10] and KIAA0319^[9][11] on chromosome 6,^[12][13] DYX1C1 on chromosome 15,^[9][12] ROBO1,^[14] DYX3,^[15] the language-disorder candidate gene CMIP,^[16] and several others. However, these genes account for a small proportion of variance in reading disability, often less than 0.5%.^[17][18] Additionally, the findings are not always replicated. Therefore, no single gene is definitively implicated in dyslexia. A 2007 review reported that no specific cognitive processes are known to be influenced by the proposed genes.^[19]

It is likely that multiple genes, as well as the environment, interact to influence reading ability. The Generalist Genes Hypothesis proposes that many of the same genes are implicated within different aspects of a learning disability as well as between different learning disabilities. Indeed, there also appear to be a large genetic influence on other learning abilities, such as language skills.^[20] The Generalist Genes Hypothesis supports the findings that many learning disabilities are comorbid, such as speech sound disorder, language impairment, and reading disability,^[21] although this is also influenced by diagnostic overlap.

Many of the genes implicated in dyslexia play a role in general neural development. For example, dyslexia candidate genes DYX1C1, ROBO1 KIAA0319, and DCDC2 appear to be involved in neuronal migration.^{[10][22][23][24]} Animal models are especially useful in determining the function of these genes. For example, Gene knockdown in utero of DYX1C1 disrupts hippocampal development and causes impairments in auditory processing and spatial learning in rodents^[25] and mutations in DCDC2 impairs visuo-spatial memory, visual discrimination, and long-term memory in mice.^[26] The role of neuronal migration in dyslexia is reviewed in Galaburda (2005).^[27]

Genes and chromosomes associated with dyslexia

Molecular studies have linked several forms of dyslexia to genetic markers.^[28] Several candidate genes have been identified, including at the two regions first related to dyslexia: ROBO1^[29] on chromosome 3, DCDC2^[10][29] and KIAA0319,^[11][29] on chromosome 6,^[30] DYX1C1^[29] on chromosome 15 and PCDH11X^[31] on chromosome X.

A 2007 review reported that no specific cognitive processes are known to be influenced by the proposed susceptibility genes. Some studies have already started to include neurophysiological (e.g., event-related potential) and imaging (e.g., functional MRI) procedures in their phenotype characterisation of patients. Such samples are an important prerequisite for the identification of those processes that are most proximal to the effects of particular genes and their associated biological pathways.^[32]

References