Alternative titles; symbols
Other entities represented in this entry:
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.3 | {Dyslexia, susceptibility to, 1} | 127700 | Autosomal dominant | 3 | DNAAF4 | 608706 |
A number sign (#) is used with this entry because of evidence that variation in the DYX1C1 gene (DNAAF4; 608706) may be the basis of the form of dyslexia (DYX1) that maps to chromosome 15q21.
Dyslexia is a disorder manifested by difficulty learning to read despite conventional instruction, adequate intelligence, and sociocultural opportunity. It is among the most common neurodevelopmental disorders, with a prevalence of 5 to 12%. Although there is evidence for familial clustering and heritability, the disorder is considered a complex multifactorial trait (Schumacher et al., 2007).
Genetic Heterogeneity of Susceptibility to Dyslexia
Additional dyslexia susceptibility loci include DYX2 (600202) on chromosome 6p22, DYX3 (604254) on chromosome 2p16-p15, DYX5 (606896) on chromosome 3p12-q13, DYX6 (606616) on chromosome 18p11.2, DYX8 (608995) on chromosome 1p36-p34, and DYX9 (300509) on chromosome Xq27.3.
See MAPPING for other possible dyslexia susceptibility loci, including DYX4 and DYX7.
Shaywitz et al. (1992) challenged the view of dyslexia as a biologically based disorder distinct from other less specific reading problems. According to this view, reading ability was considered to follow a bimodal distribution, with dyslexia as the lower mode. Shaywitz et al. (1992) contended that reading ability follows a normal distribution, with dyslexia at the lower end of the continuum. They presented data they interpreted as supporting their hypothesis. The argument was reminiscent of that which surrounded the genetics of essential hypertension (145500) 30 years earlier.
Merzenich et al. (1996) and Tallal et al. (1996) described adaptive training exercises mounted as computer 'games' which demonstrated fundamental aspects of language-based learning impairment and suggested an approach to therapy. The work was based on evidence that language-based learning impairment (LLI) results from a basic deficit in processing rapidly changing sensory inputs. Specifically, LLI children commonly cannot identify fast elements embedded in ongoing speech that have durations in the range of a few tens of milliseconds, a critical time frame over which many phonetic contrasts are signaled. Normally, exposure to a specific language alters an infant's phonetic perceptions within the first months of life, leading to the setting of prototypic phonetic representations, the building blocks on which a child's native language develops. LLI is thought to represent a phonologic processing deficit. Merzenich et al. (1996) and Tallal et al. (1996) found that LLI children receiving extensive daily training over a period of weeks with listening exercises in which all speech was translated into a synthetic form showed improvement in their 'temporal processing' skills. From these studies, the authors concluded that there may be no fundamental defect in the learning machinery in most dyslexic children. Their conclusion suggests in turn that the physical differences and distributed functional response differences revealed in evoked potential and imaging studies of the brain of LLI individuals may be effects of the learning histories of these children. Furthermore, it may imply that inherited factors contributing to the origin of LLI may relate to the initiation of a scenario that embeds, through learning, a defective representation of speech phonetics, and does not necessarily mean that these children have irreversible defects in the molecular and cellular elements of the learning machinery of their brains.
Svensson et al. (2011) reported a large 6-generation Swedish family in which 16 adults and 6 children (35% of total family members) had dyslexia. Ten family members had an uncertain diagnosis, and thirty family members had normal reading skills. All family members showed normal educational achievement. Males were more often affected than females. Genomewide linkage analysis did not identify a candidate region, and previous linkage studies to various candidate loci were not replicated. The studies suggested that the transmission of dyslexia in this family was not due to a highly penetrant major gene, but Svensson et al. (2011) noted that the power may have been too small to confirm linkage to genes with small or moderate effects.
Galaburda and Kemper (1978) described cytoarchitectonic abnormalities in the left cerebral hemisphere and posterior language area on the left in a 20-year-old man with severe reading disability and a family history of the same.
Pennington et al. (1987) found no increased frequency of left-handedness or of immune disorders in familial dyslexics.
Eden et al. (1996) identified a biologic marker for dyslexia: a striking difference in the brain activity of adults with developmental dyslexia compared to that of controls. The physiologic anomaly, revealed by functional magnetic resonance imaging (MRI), was elicited in probands by their viewing of moving dots. The findings revealed differences in the regional functional organization of the cortical visual system in dyslexia. Frith and Frith (1996) discussed the significance of the findings.
Learning to read requires an awareness that spoken words can be decomposed into the phonologic constituents that the alphabetic characters represent. Such phonologic awareness is characteristically lacking in dyslexic readers who, therefore, have difficulty mapping the alphabetic characters onto the spoken word. To find the location and extent of the functional disruption in neural systems that underlies this impairment, Shaywitz et al. (1998) used functional MRI to compare brain activation patterns in dyslexic and nonimpaired subjects as they performed tasks that made progressively greater demands on phonologic analysis. Brain activation patterns differed significantly between the groups, with dyslexic readers showing relative underactivation of posterior regions (Wernicke area, the angular gyrus, and striate cortex) and relative overactivation in an anterior region (inferior frontal gyrus). Based on these results, Shaywitz et al. (1998) concluded that the impairment in dyslexia is phonologic in nature and that the brain activation patterns may provide a neural signature for this impairment.
Research has suggested that a fundamental deficit in dyslexia is the inability to process sensory input that enters the nervous system rapidly and that deficits in processing rapid acoustic information are associated with impaired reading. Temple et al. (2000) used functional magnetic resonance imaging to identify the brain basis of rapid acoustic processing in normal readers and to discover the status of that response in dyslexic readers. Normal readers showed left prefrontal activity in response to rapidly changing, relative to slowly changing, nonlinguistic acoustic stimuli. Dyslexic readers showed no differential left frontal response. Two dyslexic readers participated in a remedial program and showed increased activity in the left prefrontal cortex after training. These results identified left prefrontal regions as normally being sensitive to rapid relative to slow acoustic stimulation, insensitive to the difference between such stimuli in dyslexic readers, and plastic enough in adulthood to develop such differential sensitivity after intensive training.
Temple et al. (2003) examined whether behavioral remediation ameliorates the dysfunction of neural mechanisms underlying phonologic processing in children with dyslexia. Functional MRI was performed on 20 children with dyslexia (aged 8 to 12 years) during phonologic processing before and after a remedial program focused on auditory processing and oral language training. Behaviorally, training improved oral language and reading performance. Physiologically, children with dyslexia showed increased activity in multiple brain areas. The results suggested that a partial remediation of language-processing deficits, resulting in improved reading, ameliorates disrupted function in brain regions associated with phonologic processing and produces additional compensatory activation in other brain areas.
Hallgren (1950) studied 116 families with dyslexia. Speech defects were associated in many instances, especially in males, and were probably determined by the same factor as dyslexia. Left-handedness and left-eyedness could not be shown to be associated. Genetic analysis suggested autosomal dominant inheritance. Zahalkova et al. (1972) concluded that dyslexia is inherited as an autosomal dominant with reduced penetrance in females. Finucci et al. (1976) studied the immediate family of 20 children with specific reading disability. Forty-five percent of 75 first-degree relatives were considered affected on the basis of a procedure that identified an adult who might have compensated for a disability manifested more clearly in childhood. They proposed heterogeneity in this disorder and were reluctant to espouse any single mode of inheritance.
From multiple regression analysis of data on 64 pairs of identical twins and 55 pairs of fraternal twins, DeFries et al. (1987) presented evidence for a significant genetic etiology.
In a review, Schumacher et al. (2007) stated that cumulative studies have found that a child with an affected parent has a 40 to 60% risk of developing dyslexia. In addition, there is an estimated 3 to 10-fold increase in the relative risk for dyslexia in a sib with an affected sib.
DYX1 on Chromosome 15q
Smith et al. (1983) studied linkage of autosomal dominant specific reading disability in 9 families and demonstrated a total lod score of 3.241 with chromosome 15 heteromorphisms. One family contributed 2.755 to the total and 2 others had negative lod scores; however, tests for linkage heterogeneity did not reach significance. Maximum lod scores were at theta = 0.0. Chromosome analysis was done by sequential Q-to-C banding. Further studies (Fain et al., 1985) reduced the lod score to values below 3.0. In Danish studies, Bisgaard et al. (1987) found negative lod scores for linkage of dyslexia and chromosome 15 heteromorphism. In a study of nine 3-generation families in which dyslexia appeared to be inherited as an autosomal dominant trait with a high degree of penetrance, Rabin et al. (1993) excluded linkage to proximal 15q in all families. The family that had previously provided most of the lod score for chromosome 15p in the study of Smith et al. (1983) was independently restudied and included in the 9 families. A screen of other regions of the genome revealed possible linkage to RH (111700). Two DNA markers, also localized to 1p36-p34, similarly yielded positive lod scores in all families (see 608995). Froster et al. (1993) described a family in which a t(1;2)(p22;q31) translocation cosegregated with retarded speech development and dyslexia.
Grigorenko et al. (1997) reported linkage for distinct components of dyslexia to chromosomes 6 and 15: the phonologic-awareness phenotype was mapped to 6p22-p21, and the single word-reading phenotype was assigned to 15q21. The single word-reading phenotype showed linkage to marker D15S143 with a lod score of 3.15 at theta = 0.0, under an autosomal dominant inheritance model. Schulte-Korne et al. (1998) studied linkage of another component of dyslexia, namely, spelling disability, in 7 multiplex German families. Twin studies had indicated that deficits in spelling are substantially heritable and that the heritability of spelling deficits is higher than the heritability of reading deficits (Stevenson et al., 1987; DeFries et al., 1991). The results of Schulte-Korne et al. (1998) confirmed linkage between 15q21 markers and dyslexia. The results did not support a strong effect by a putative chromosome 6 dyslexia gene on the phenotype of spelling disability. The gene on chromosome 15 seems to be relevant for both spelling and word reading. Spelling and reading disability had been known to be strongly correlated.
Morris et al. (2000) used family-based association mapping to further pursue linkage between reading disability (RD) and the region on chromosome 15q. RD was defined as having an IQ greater than 85 and being at least 2.5 years behind chronological age in reading. A significant association was detected between RD and a 3-marker haplotype (D15S994/D15S214/D15S146: P and empirical P less than 0.001) in 101 parent-proband trios, as well as in a second-stage sample of 77 additional trios (P = 0.009, empirical P = 0.006). The authors concluded that there may be 1 or more genes contributing to RD in the vicinity of D15S146 and D15S994, and showed the utility of association analysis in mapping susceptibility loci for complex disorders.
To confirm linkage of continuous measures of (1) accuracy and efficiency of phonologic decoding, and (2) accuracy of single word reading, to regions on chromosomes 2p, 6p, 15p, and 18p, Chapman et al. (2004) studied 111 families, identified through a child with reading difficulties, with a total of 898 members. Evidence for linkage of single word reading to chromosome 15q was found with a maximum single marker perimetric lod score of 2.34 located 3 cM from D15S143. Multipoint analysis localized the putative susceptibility gene to an interval between markers GATA50C03 and D15S143.
In a sample of 121 Italian parent-offspring families, Marino et al. (2004) used a transmission/disequilibrium approach to confirm previous findings of an involvement of the 15q15-qter region in developmental dyslexia.
Taipale et al. (2003) characterized a gene, DYX1C1 (608706), near the DYX1 locus in 15q21 that was disrupted by a translocation t(2;15)(q11;q21) segregating coincidentally with dyslexia in a family described by Nopola-Hemmi et al. (2000). They found 2 sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (-3G-A; 608706.0001) and the other a transversion (1249G-T; 608706.0002) introducing a premature stop codon and truncating the predicted protein by 4 amino acids.
Using quantitative transmission disequilibrium test analysis, Meng et al. (2005) found no association between the 2 polymorphisms reported by Taipale et al. (2003) in the DYX1C1 gene and 150 nuclear families with dyslexia from Colorado.
DYX4 on Chromosome 6q
Using a qualitative phonologic coding dyslexia phenotype to categorize 96 families with dyslexia, Petryshen et al. (2001) found evidence for a susceptibility locus, termed DYX4, on chromosome 6q11.2-q12. Two-point parametric analysis yielded maximum lod scores ranging from 2.4 to 2.8 across an 11-cM region. Analysis of phonologic coding and spelling yielded peak lod scores of 2.1 and 3.3, respectively, under 2 degrees of freedom, at marker D6S965.
DYX7 on Chromosome 11p
Using model-free linkage analysis to study 100 families with dyslexia, Hsiung et al. (2004) found evidence for linkage to the DRD4 (126452) exon 3 repeat on chromosome 11p15.5 (2-point lod score of 2.27). Evidence for linkage was also found to HRAS (190020), located just proximal to DRD4 (2-point lod score of 2.68). The locus was termed DYX7.
Possible Locus on Chromosome 7q32-q33
Kaminen et al. (2003) performed a genomewide scan in 11 Finnish families containing 38 patients with dyslexia. A novel locus at chromosome 7q32 close to the FOXP2 gene (605317) was suggested by a nonparametric linkage score of 2.77. The authors noted that mutation in the FOXP2 gene had previously been found to cause a severe speech and language disorder (SPCH1; 602081) with some overlap in language deficits to dyslexia. They therefore screened the FOXP2 gene in 6 of the dyslexic patients, but identified no mutations.
By fine mapping studies of the 7q32 region in the original Finnish families reported by Kaminen et al. (2003), Matsson et al. (2011) refined the candidate region to a 0.3-Mb region on chromosome 7q31-q34 (maximum nonparametric lod score of 2.4). Similar mapping studies on 251 German dyslexic families did not yield definitive results for this region. Association studies were then performed on the German families, the original Finnish families, and an extended group of Finnish families including 153 additional dyslexic individuals. A haplotype spanning intron 1 to 3 of the DGKI gene (604072) showed a moderate association with dyslexia in the transmission disequilibrium test (p = 0.04) in the Finnish families. This haplotype overlapped on 2 markers with a significantly associated haplotype (p = 0.00093) from the German sample. The haplotype in the German sample spanned introns 5 to 8 of the DGKI gene and the association was borderline significant after Bonferroni correction (p = 0.054).
Rosenberger (1992) provided a brief historical overview of dyslexia.
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