Molecular Genetic Approaches To Locating The Genes For Dyslexia

Behavioral comparisons of MZ and DZ twins have yielded valuable information about the balance of genetic and environmental influence on group deficits in reading and related language skills. Further analyses of genetic influence on reading disabilities in relation to IQ and other individual characteristics will provide more specific information about this balance across individuals. However, the further specification and understanding of genetic mechanisms at the individual level will ultimately depend on the identification of specific genes that are associated with reading disability.

A first step in locating genes that influence dyslexia is to find regions on chromosomes that are likely to carry those genes. This is done through a method called linkage analysis. DNA markers (not necessarily genes) that vary across individuals are identified in a region of interest. Siblings that share or do not share dyslexia are then compared on whether they share or do not share the specific marker. If sharing the marker means it is significantly more likely that they also share dyslexia, there is linkage evidence for dyslexia in that region. However, the identified region on a chromosome may be very broad and contain many genes. Linkage only shows that having inherited the same large region of DNA on a chromosome from their parents, the siblings are more likely to share dyslexia.

Recent linkage analyses suggest that a gene or genes on the short arm of chromosome 6, close to the HLA region, may account for a significant proportion of reading disabilities. Preliminary evidence for this linkage was first obtained by Smith, Pennington, and Kimberling (1991) using data from 19 extended families with a history of reading problems. Cardon et al. (1994) applied more powerful linkage analyses to these family data and added a sample of 46 DZ twin families from the Colorado Reading Project. Taken together, the extended family and twin data provided highly significant evidence for a genetic linkage to reading disability near the HLA region of chromosome 6.

Reading disability in the above linkage studies was ascertained through a composite measure of word recognition, reading comprehension, and spelling from the Peabody Individual Achievement Test (Dunn & Markwardt, 1970). Gayan et al. (1999) used the same analytic methods with an expanded DZ twin and sibling sample to look for linkage to deficits in the specific skills of phoneme awareness, phonological decoding, orthographic coding, and fluent word recognition. These results suggest that deficits in phoneme awareness, phonological decoding, and orthographic coding show strong evidence for linkage to genetic markers in the HLA region of chromosome 6. The evidence was less strong for two measures of word recognition.

A similar pattern of linkage results for phoneme awareness and word recognition has been reported by Grigorenko et al. (1997). They used data from extended families with a history of reading disabilities and found strong linkage for deficits in phoneme awareness to the same HLA region of chromosome 6. Linkage appeared to be weaker in this region for deficits in word recognition, which were more strongly linked to a region on chromosome 15. The possibility of differential genetic linkages for different component skills in reading and language is intriguing, but a much larger subject sample is needed to test the statistical significance of these differences. This additional data is now being collected by our Center, with additional genetic markers including other regions of the genome.

Most recently, DNA from the Colorado sample and an independent sample collected in England were subjected to a whole-genome scan to search for linkage in other regions. Fisher et al. (2002) found evidence in both samples for linkage to the HLA region on chromosome 6, and even stronger evidence for linkage in both samples to a region on chromosome 18. A strong genetic linkage for deficits in phoneme awareness and orthographic coding has now been confirmed in two independent laboratories for the same regions of chromosomes 6 and 18.

A different approach to finding genes related to dyslexia is to see if genes already identified, which are known to be expressed in the brain, have variations (called alleles) that are associated with dyslexia. One example of this approach was used by Smith et al. (2001). They looked at different alleles of a gene called MOG in the same region of chromosome 6 that had been supported in previous linkage studies for dyslexia. Unfortunately, the variations in this gene were not significantly associated with dyslexia. Franks et al. (2002) looked for association of dyslexia with two genes in a region of chromosome 2 that were in a region that had been previously identified in linkage studies. They also failed to find allelic variations in these genes that were associated with dyslexia. Another related approach is to find variations in DNA that are close enough to a responsible gene that they are nearly always inherited with the gene. This procedure was used by Kaplan et al.

(2002). They found preliminary evidence for association with a marker on chromosome 6 in the same region identified by linkage studies. If this result can be confirmed in other independent samples, it could serve as an identifiable marker that is associated with some proportion of the genetic risk for dyslexia.

Once genes that have alleles associated with dyslexia are identified, the real hard work begins. The next steps are to clone the gene(s), identify the coded protein(s), and determine the influence of the protein(s) on the developing nervous system and related behavior, in interaction with the environment. Much more research will be needed to reach the last two goals, but recent advances in methods for locating genes and related markers may soon allow us to identify individuals who have a gene or genes that place them at risk for reading disability. Early information about a genetic risk could be used to provide additional support in a child's early language and reading environment. Providing support prior to school entry could help avoid the stigmatizing effect of school failure in reading.

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Adult Dyslexia

Adult Dyslexia

This is a comprehensive guide covering the basics of dyslexia to a wide range of diagnostic procedures and tips to help you manage with your symptoms. These tips and tricks have been used on people with dyslexia of every varying degree and with great success. People just like yourself that suffer with adult dyslexia now feel more comfortable and relaxed in social and work situations.

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