Key Points
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Despite decades of multidisciplinary investigation, the biological basis of dyslexia — a specific impairment of reading ability — remains obscure. But a series of recent studies has emphasized the contribution of genetic factors to this disorder.
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Dyslexia runs in families, and studies of monozygotic and dizygotic twins have provided valuable insights into the heritability of the condition. Methods developed for these studies have also aided in the genetic mapping of this reading disability.
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For several reasons, the genetic analysis of dyslexia is complex. For example, there is no straightforward correspondence between genotype and phenotype, and phenotypic variations can depend on the developmental stage of the subject. Similarly, there is a lack of consensus on the definition of dyslexia, and on whether it is a single trait or a cluster of traits with distinct aetiologies.
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Successful localization of genes that influence dyslexia has been aided by innovations in three areas. First, methods have been developed for mapping genes that contribute to quantitative variability in reading performance. Second, researchers are dissecting the phenotypic profile into distinct but related components for genetic study. Third, it is now possible to scan all chromosomes of the genome when searching for genes that influence complex traits such as dyslexia.
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Targeted linkage studies of dyslexia have provided strong evidence that two chromosomal regions — 15q21 and 6p21 — are involved in this syndrome. Similarly, genome-wide scans have identified further regions on chromosomes 2, 3 and 18 that seem to be linked to dyslexia in multiple independent sets of families.
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Although the linkage results highlight chromosomal regions that are involved in dyslexia susceptibility, finding individual genes that are affected remains a daunting task. So far, no specific dyslexia gene has been identified, but studies of speech and language deficits have found a gene — FOXP2 — that is responsible for a rare form of the disorder.
Abstract
Developmental dyslexia, a specific impairment of reading ability despite adequate intelligence and educational opportunity, is one of the most frequent childhood disorders. Since the first documented cases at the beginning of the last century, it has become increasingly apparent that the reading problems of people with dyslexia form part of a heritable neurobiological syndrome. As for most cognitive and behavioural traits, phenotypic definition is fraught with difficulties and the genetic basis is complex, making the isolation of genetic risk factors a formidable challenge. Against such a background, it is notable that several recent studies have reported the localization of genes that influence dyslexia and other language-related traits. These investigations exploit novel research approaches that are relevant to many areas of human neurogenetics.
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Acknowledgements
S.E.F. is a Royal Society Research Fellow. J.C.D. is supported by a centre grant from the National Institute of Child Health and Human Development.
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FURTHER INFORMATION
Encyclopedia of Life Sciences
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FOXP2 in Speech and Language Disorder
Glossary
- PHONEMES
-
Individual units of speech sound that combine to make words.
- MENDELIAN
-
A trait resulting from changes in a single gene that has a significant effect on the phenotype and is inherited in a simple pattern that is similar or identical to those described by Gregor Mendel. Also referred to as monogenic.
- PROBAND
-
Usually, the person who serves as the starting point of a genetic study.
- MONOZYGOTIC
-
Twins that develop from a single fertilized egg cell through its division into two genetically identical parts.
- DIZYGOTIC
-
Twins that develop during the same pregnancy as the result of two separate eggs being fertilized by two separate sperm.
- HERITABILITY
-
The proportion of variability in a particular characteristic that can be attributed to genetic influences. This is a statistical description that applies to a specific population and might change if the environment is altered.
- SPECIFIC LANGUAGE IMPAIRMENT
-
A significant deficit in language development in children with normal non-verbal intelligence that cannot be attributed to hearing loss, inadequate educational opportunity or obvious neurological impairment.
- ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
-
A common disorder with childhood onset, in which persistent inattention and/or hyperactive–impulsive behaviour leads to impaired social and/or academic functioning.
- CANDIDATE GENE
-
A gene that encodes a protein, the expected or known function of which indicates that it might be responsible for a disease or trait in a population of individuals. Pure candidate-gene approaches do not exploit or require information on chromosomal location (in contrast to 'positional cloning').
- POLYMORPHIC GENETIC MARKERS
-
Naturally occurring variants in DNA sequence that can be used to track the inheritance pattern of a particular chromosomal location.
- POSITIONAL CLONING
-
A strategy for the identification of disease genes on the basis of marker inheritance data from affected families that does not require any prior knowledge of the underlying biological pathways or gene function (in contrast to 'candidate-gene' approaches). In recent years, a blend of positional cloning and candidate-gene approaches (sometimes referred to as a 'positional-candidate' strategy) has often been used, involving the combined use of data on map location and expected gene function.
- GENOTYPE
-
The genetic constitution of an individual. This can refer to the entire complement of genetic material or to a specific gene (or set of genes).
- PHENOTYPE
-
The appearance of an individual in terms of a particular characteristic (physical, biochemical, physiological and so on), resulting from interactions between the individual's genotype and the environment.
- PENETRANCE
-
The probability that an individual with a particular genotype manifests a given phenotype. Complete penetrance corresponds to the situation in which every individual with the same specific genotype manifests the phenotype in question.
- PHENOCOPIES
-
People who manifest the same phenotype as other individuals of a particular genotype, but do not possess this genotype themselves. For example, this might occur when environmental influences alone evoke a developmental trait that has a similar genetic counterpart.
- OLIGOGENICITY
-
When a few different genes work together to contribute to a particular phenotype.
- POWER
-
The probability of correctly rejecting the null hypothesis when it is truly false. For linkage studies, the null hypothesis is that of 'no linkage', so the power represents the probability of correctly detecting a genuine linkage.
- QUANTITATIVE TRAIT LOCUS
-
(QTL). A genetic locus or chromosomal region that contributes to variability in a complex quantitative trait (such as body weight), as identified by statistical analysis.
- POLYGENIC
-
The effects of a large number of different genes, each of which has a slight influence on the phenotypic outcome.
- GRAPHEME
-
A written symbol, or group of symbols, that is used to represent a specific phoneme.
- MULTIPOINT ANALYSIS
-
The use of data obtained from multiple neighbouring genetic markers on the same chromosome to extract linkage information at many points across a genomic region.
- SINGLE-POINT ANALYSIS
-
The investigation of linkage at one point on a chromosome, using data from a single marker.
- LOD SCORE
-
Linkage mapping involves comparing two likelihoods. The first is the likelihood of the data, under the hypothesis that there is linkage between inheritance of the trait and that of the chromosomal region in question. The second is the likelihood of the data, under the null hypothesis that there is no linkage. The lod score is the logarithm of the likelihood ratio; if it exceeds a given threshold, the null hypothesis can be rejected.
- CHROMOSOMAL HETEROMORPHISM
-
Natural variation in the shape or staining pattern of a chromosome, as viewed under the microscope.
- CENTROMERE
-
The constricted region of a chromosome that includes the site of attachment to the mitotic or meiotic spindle. Geneticists divide the chromosome into 'short' and 'long' arms, which are separated by this centromere.
- CENTIMORGAN
-
A standard measure of genetic distance that is derived from observations of recombination between neighbouring loci. The relationship to actual physical distance along a chromosome varies throughout the genome; on average, 1 centimorgan corresponds to around one million bases of DNA.
- HLA COMPLEX
-
A well-studied region of chromosome 6p that contains many loci, such as the human leukocyte antigen (HLA) genes, which encode key components of the immune system. Also known as the major histocompatibility complex (MHC).
- AUTOSOMAL DOMINANT
-
One type of inheritance pattern that is observed for monogenic traits. Autosomes are any chromosomes in a cell that are not sex chromosomes. Autosomal dominant transmission results when an abnormal copy of an autosomal gene from a single parent gives rise to the trait, even though the copy inherited from the other parent is normal.
- TRANSLOCATION
-
A genetic rearrangement in which part of a chromosome is detached by breakage and becomes attached to another part of the same chromosome, or to a different chromosome.
- DUPLICATION
-
A genetic rearrangement that involves the doubling or repetition of part of a chromosome.
- DELETION
-
A genetic rearrangement that involves the loss of part of a chromosome.
- INVERSION
-
A genetic rearrangement in which part of a chromosome is reversed, so that the genes within that part are in inverse order.
- BREAKPOINT
-
The specific site of chromosomal breakage that is associated with a particular chromosomal rearrangement.
- LINKAGE DISEQUILIBRIUM
-
Non-random association between specific allelic variants at one genetic locus and those at another genetic locus that maps nearby.
- EFFECT SIZE
-
A standardized measure of effect that is adopted when different scales are used to measure an outcome. In QTL analyses, the effect size is the proportion of variability in a measure that is attributable to the genetic locus of interest.
- TRANSCRIPTION FACTOR
-
A DNA-binding protein that regulates gene expression.
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Fisher, S., DeFries, J. Developmental dyslexia: genetic dissection of a complex cognitive trait. Nat Rev Neurosci 3, 767–780 (2002). https://doi.org/10.1038/nrn936
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DOI: https://doi.org/10.1038/nrn936
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