Alternative titles; symbols
DO: 4428;
Cytogenetic location: 6p22-p21 Genomic coordinates (GRCh38): 6:15,200,001-46,200,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22-p21 | {Dyslexia, susceptibility to, 2} | 600202 | Autosomal dominant | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of susceptibility loci for dyslexia, see DYX1 (127700).
Cardon et al. (1994) reviewed previous linkage studies. Suggestion of linkage on chromosome 15 was later not confirmed. They referred to evidence of possible linkage to markers in the RH region of chromosome 1 and linkage with a translocation between 1p and 2q. A preliminary finding of linkage to the HLA region of chromosome 6 was confirmed in a study of the same kindreds by use of more informative markers and was replicated in an independent sample of dizygotic twins. The HLA region had been targeted because of a possible association between dyslexia and autoimmune disorders. The kindred sample comprised 19 families with a pattern of the disorder consistent with autosomal dominant inheritance. The twin sample comprised 50 families. One advantage of using DZ twins for linkage analysis is that they provide a perfect control for the effects of age. Results obtained from analyses of reading performance in 114 sib pairs localized the quantitative trait locus (QTL) for reading disability to 6p21.3. Analyses of corresponding data from the sample of 50 DZ twin pairs provided evidence for linkage to the same region. In combination, the 2 samples yielded a chi square value of 16.73 (p = 0.0002). Examination of twin and kindred sibs with more extreme deficits in reading performance yielded even stronger evidence for a QTL. The position of the QTL was narrowly defined with a 100:1 confidence interval to a 2-cM region between markers D6S105 and TNFB (153440).
When Smith et al. (1991) omitted 1 family with strong linkage to the centromeric region of chromosome 15, the remaining families with dyslexia revealed linkage to markers BF (138470) on 6p21.3 and GLO1 (138750), which maps to the same area in or just proximal to the HLA region.
Grigorenko et al. (1997) interpreted the results of their linkage studies as supporting the chromosome 6p linkage reported by Cardon et al. (1994).
The results of Schulte-Korne et al. (1998) did not support a strong effect by a putative chromosome 6 dyslexia gene on the phenotype of spelling disability, although a gene on chromosome 15 seemed to be relevant for both spelling and word reading. Spelling and reading disability had been known to be strongly correlated.
Field and Kaplan (1998) investigated 79 families having at least 2 sibs affected with phonologic coding dyslexia, the most common form of reading disability, and tested for linkage with genetic markers reported to be linked to dyslexia in studies pointing to linkage to 6p23-p21.3. No evidence for linkage was found by lod score analysis or affected-sib-pair methods. However, using the affected-pedigree-member (APM) method, they detected significant evidence for linkage and/or association with some markers when they used published allele frequencies with weighing of rarer alleles. APM results were not significant when they used marker allele frequencies estimated from parents. Furthermore, results were not significant with the more robust SIMIBD method, which theoretically is less sensitive to misspecification of marker allele frequencies. Finally, family-based association analysis using the AFBAC program showed no evidence for association with any marker. Field and Kaplan (1998) concluded that the APM method should be used only with extreme caution, because it appears to have generated false-positive results.
Fisher et al. (1999) used QTL methods to evaluate linkage to 6p25-p21.3 in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. Analyses suggested the presence in 6p21.3 of a QTL influencing multiple components of dyslexia and affecting both phonologic and orthographic skills and not specific to phoneme awareness, as had previously been suggested. Gayan et al. (1999) likewise performed QTL studies of reading disability, using a new sample of 126 sib pairs. Results indicated significant linkage across a distance of at least 5 cM on 6p for deficits in orthographic (lod = 3.10) and phonologic (lod = 2.42) skills, confirming previous findings.
Fisher et al. (2002) found continuing support for a role for 6p21.3 in reading disability, but a newly identified QTL on 18p11.2 (606616) made a much more significant contribution to dyslexia susceptibility.
To characterize further the linkage of dyslexia to the QTL on 6p, and to identify a peak of association, Kaplan et al. (2002) did linkage analyses, as well as transmission disequilibrium, total association, and variance components analyses, on 11 quantitative reading and language phenotypes. They genotyped 104 families with reading disability using a new panel of 29 markers that spanned 9 Mb of the critical region of 6p22-p21.3. Multipoint analysis suggested a linkage peak near D6S461. Average 6p QTL heritability for the 11 reading and language phenotypes was 0.27, with a maximum of 0.66 for orthographic choice. The orthographic choice showed a peak of transmission disequilibrium and strong evidence of total association with a particular marker.
Willcutt et al. (2002) used genetic linkage analysis to assess the etiology of comorbidity between reading disability and attention-deficit hyperactivity disorder (ADHD; 143465), 2 common childhood disorders that frequently occur together. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and 3 measures of reading disability, indicating that comorbidity between reading disability and ADHD may be due at least in part to pleiotropic effects of a QTL on 6p.
The region immediately telomeric to the HLA class I (see 142800) region of the major histocompatibility complex on 6p21.3-p22 is characterized by a large interval of recombination suppression with the potential to greatly complicate precise localization of risk loci. Ahn et al. (2002) provided information on precise marker order and distances, and constructed a marker panel that framed an inversion of recombination frequency that had distorted the resolution of linkage studies for 6p loci, such as reading disability.
Replication of linkage results for complex traits, such as developmental dyslexia, is exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and limitations of the statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage. Marlow et al. (2003) conducted multivariate genomewide analyses of QTLs that influence reading- and language-related measures in families affected with developmental dyslexia and used in previous analyses. The results of these multivariate analyses were substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. For chromosome 6, the multivariate analysis outperformed all of the univariate analyses. Marlow et al. (2003) thus showed that multivariate linkage analysis could be used for dissection of such a complex cognitive trait as developmental dyslexia.
By linkage and association analyses, Deffenbacher et al. (2004) refined the 6p21.3 QTL influencing dyslexia. Several candidate genes located in the critical linkage region were excluded.
Association with the KIAA0319 Gene
In 223 sibs from the United Kingdom with reading disability, Francks et al. (2004) used association analysis to identify an underlying QTL on 6p22.2. The association study implicated a 77-kb region spanning the TTRAP gene (605764) and the first 4 exons of the neighboring uncharacterized gene KIAA0319 (609269). The region of association was also directly upstream of a third gene, THEM2 (615652). Evidence of these associations was found in a second sample of sibs from the United Kingdom, as well as in an independent sample of twin-based sibships in Colorado. One main risk haplotype (1-1-2) for reading disability that had a frequency of approximately 12% was found in both the U.K. and U.S. samples: the 1-1-2 haplotype was composed of the rs4504469, rs2038137, and rs2143340 SNPs. As the haplotype was not distinguished by any protein-coding polymorphisms, Francks et al. (2004) suggested that the functional variation may relate to gene expression.
Cope et al. (2005) attempted to identify the gene responsible for the linkage of dyslexia to 6p; they gave the critical location as a 575-kb region on 6p22.2. They performed a systematic, high-density linkage disequilibrium screen of genes within the region in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability (RD). Using DNA pooling, they first observed evidence for association with 17 SNPs, of which 13 were located in the KIAA0319 gene (609269). In a semi-independent sample of 143 trios of probands with developmental dyslexia and their parents, 6 SNPs showed significant evidence of association, including an SNP in exon 4 of the KIAA0319 gene that changed an amino acid (A311T, rs4504469). These and other data led to the conclusion that KIAA0319 is a susceptibility gene for dyslexia. The gene product is expressed in brain.
By pairwise comparison of risk and non-risk BAC sequences spanning the 77-kb RD-associated region reported by Francks et al. (2004), Dennis et al. (2009) identified 7 SNPs in the KIAA0319 promoter region. The minor allele of rs9461045 was associated with reading disability in a U.K. cohort of 264 families previously studied by Francks et al. (2004) (p values ranging from 0.0003 to 0.01). By in vitro expression assay in human neuroblastoma and embryonic kidney cells, Dennis et al. (2009) showed that the minor allele of rs9461045 in the KIAA0319 promoter region resulted in decreased KIAA0319 expression through creation of a binding site for the transcription silencer OCT1 (POU2F1; 164175). RNAi-mediated knockdown of OCT1 resulted in increased KIAA0319 expression in both neuronal and nonneuronal human cell lines.
Among individuals of white European ancestry, Paracchini et al. (2008) found that the minor allele of rs2143340 in the TTRAP gene was significantly associated with poor performance in reading and spelling (p = 0.03 to 0.003). The association was stronger when adjusted for IQ greater than 90. The 1-1-2 haplotype (rs4504469, rs2038137, and rs2143340) also showed an association with poor performance (p = 0.05 to 0.005). The findings indicated that genetic variation affecting expression of the KIAA0319 gene is not restricted to individuals with dyslexia, but may also affect reading ability in the general population.
In 48 Caucasian probands with dyslexia, Elbert et al. (2011) found evidence for a mild association between the disorder and several putative functional variants in the 5-prime region of the KIAA0319 gene, but the p values were not corrected for multiple testing. No association was found with the 2 SNPs reported by Dennis et al. (2009) (rs9461045 and rs3212236). A haplotype in the 5-prime region of KIAA0319, including microsatellite marker JA04 and a 26-bp ins/del (rs71815143), was associated with dyslexia (p = 0.0067 for JA04) in the cohort. Elbert et al. (2011) suggested that variation in the expression of KIAA0319, which is believed to play a role in neuronal migration, may contribute to the risk of developing dyslexia.
Association with the DCDC2 Gene
In a study of 153 nuclear families with dyslexia, Meng et al. (2005) found a significant association between reading disability and several SNPs within the DCDC2 gene (605755) on chromosome 6p22. There was significant transmission disequilibrium with several reading phenotypes in the context of preserved IQ, suggesting a specific effect on reading performance. In 10 nuclear families, a 2,445-bp deletion containing a 168-bp purine-rich region in intron 2 was identified. Within the purine-rich region was a polymorphic compound short tandem repeat (STR) composed of 10 alleles containing variable copy numbers of (GAGAGGAAGGAAA)n and (GGAA)n repeat units. Database analysis identified 131 putative transcription factor binding sites distributed throughout the purine-rich region, including multiple copies of binding sites for the brain-related transcription factors PEAS3 (ETV4; 600711) and NFATP (NFATC2; 600490). Alleles of the STR were in significant disequilibrium with multiple reading traits. Strong linkage disequilibrium with reading performance (p = 0.00002) was found. Meng et al. (2005) suggested that changes in expression of DCDC2 may result in subtle functional changes in the brain.
Meng et al. (2011) examined the mechanism of the association between the conserved polymorphic purine-rich STR in intron 2 of the DCDC2 gene, which they called BV677278, and reading disability. Electrophoretic mobility shift assays showed that the BV677278 sequence bound nuclear proteins in a human brain lysate as well as in lymphoma cells. Expression of the 6 most common alleles of BV677278 in P19 cells, multipotent murine cells that can differentiate into neurons and neuroglia, showed that the alleles have a range of DCDC2-specific enhancer activities. The findings suggested that BV677278 alleles can modify DCDC2 expression to various degrees, which may link to changes in neural migration in the central nervous system.
Schumacher et al. (2006) indicated that the most frequently replicated dyslexia susceptibility region is that on 6p22-p21. They searched for linkage disequilibrium (LD) in this region in 137 triads with dyslexia. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. The association was confirmed in an independent sample of 239 triads. Schumacher et al. (2006) determined that DCDC2 is expressed in the fetal and adult central nervous system. This, together with the hypothesized function of the protein, which contains a doublecortin homology domain that may be involved in cortical neuron migration, was in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation.
Lind et al. (2010) identified associations between SNPs in the DCDC2 gene and normal variation in reading and spelling in 1,067 individuals, including 90 monozygotic and 305 dizygotic twin pairs, from 522 Australian families that were not selected for reading impairment. Significant association was found for rs1419228 in intron 9 with regular-word reading and spelling (p = 0.002) as well as irregular-word reading (p = 0.004), whereas rs1091047 in intron 4 was significantly associated with irregular-word reading (p = 0.0034). Four additional SNPs (rs9467075, rs9467076, rs7765678 and rs6922023) were nominally associated with reading and spelling. Lind et al. (2010) stated that their study supports DCDC2 as a risk gene for reading disorders and suggested that DCDC2 can act on normally varying reading skills in the general population.
Marino et al. (2011) evaluated 581 individuals from 180 nuclear Italian families, ascertained by a proband with developmental dyslexia, for various language and mathematical abilities. Probands with dyslexia tended to perform below average for the mathematics domain overall, but close to average for the language domain. Genotyping showed evidence for an association between allele 2 of DCDC2 BV677278 and 'numerical facts' (p = 0.02) in 85 informative families, but no association with language phenotypes. These findings suggested pleiotropic effects for the DCDC2 gene on reading ability and mathematical skills, but Marino et al. (2011) emphasized that the results should be interpreted with caution and need to be replicated.
By haplotype analysis of the DCDC2 region in individuals from a longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) (Boyd et al., 2013), Powers et al. (2013) identified two 6-marker haplotypes within a block in DCDC2 that were associated with reduced performance on reading and language phenotypes: CGCGAG was associated with reading disability and GACGAG was associated with language impairment. The haplotype blocks were in close proximity to and in linkage disequilibrium with alleles 5 and 6 of BV677278, which Powers et al. (2013) referred to as 'READ1' (regulatory element associated with dyslexia-1). Mass spectrometry and chromatin immunoprecipitation studies identified the transcription factor ETV6 (600618) as the READ1 binding-protein, which implicated READ1 as a regulatory element. The DCDC2 risk haplotypes showed a synergistic effect with the risk haplotype in the 5-prime region of the KIAA0319 gene; several individuals positive for risk haplotypes in both genes showed markedly worse performance on all reading and language phenotypes examined. The findings suggested that READ1 is a regulatory element that influences reading and language skills.
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