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Learning Disabilities - Genetics of Dyslexia

Dyslexia is heterogeneous and genetically complex. However, recent studies have identified potential candidate genes for dyslexia and other language-related traits. Genetics plays a major role in 40-80% of dyslexia, with a maximum role in spelling (70%) and word reading (58%). A child with an affected parent has 40-60% chance of developing dyslexia, the risk further increases if there are other affected members in the family (Stephenson, 1907; Olson et al, 1994; Ziegler et al, 2005).

Twin Studies

Twin studies indicate the role of genetic factors in the familial clustering of dyslexia (Plomin & Kovas, 2005). The first genetic evidence for the high familiarity of developmental dyslexia came in the 1980s from two key twin studies, the Colorado Twin Reading Study and the London Twin Study. In the Colorado Twin Reading Study, the genetic component of phonological processing (75%) was found to be higher when compared to that of orthographic processing (31%) (DeFries et al, 1987). In the London Twin Study, a strong association (75%) was observed for the heritability of spelling and a moderate association (44%) for reading ability (Stevenson et al, 1987). A high heritability for dyslexia was found for boys in a UK-based study (Harlaar N et al, 2005).

According to a review on twin studies of language disability there is a 75% concordance for monozygotic (MZ) twins and 43% for dizygotic (DZ) twins (Stromswold, 2001). The concordance rate for reading disability in MZ and DZ twins was found to be about 70% and 50%, respectively (Oliver et al, 2004).

Linkage studies in dyslexia

Linkage studies have identified dyslexia susceptible genes on specific chromosomal loci. HUGO Gene Nomenclature Committee has recorded nine dyslexia susceptibility loci, DYX1 to DYX9. These include,

  • DYX1 on chromosome 15q21 (MIM 127700): In 1983, Smith et al (1983) first noticed the DYX1 locus on chromosome 15q21 based on linkage to chromosome heteromorphisms (LOD score = 3.2) (Smith et al, 1983). This locus was found to be associated with word reading and related phenotypic features (Smith et al, 1983; Grigorenko & Chang, 1997; Schulte-Korne G, 1998 Chapman NH, 2004).
  • DYX2 on chromosome 6p21 (MIM 600202): Cardon et al (1994) and Smith et al (1991) first reported significant linkage of DYX2 locus (6p21.33) for dyslexia in sibling pairs and dizygotic twins (Cardon et al, 1994; Cardon et al, 1995; Smith et al, 1991). It has been reported to be associated with phonological processing (Fisher et al, 2002; Kaplan et al, 2002) and orthographic processing (Kaplan et al , 2002; Grigorenko et al, 2003). Linkage disequilibrium mapping of the DYX2 locus resulted in the detection of two strong candidate genes, KIAA0319 and doublecortin domain containing protein 2 (DCDC2), for dyslexia (Cope et al, 2005; Deffenbacher et al, 2004; Schumacher et al, 2006). Recent studies have shown that certain variations in READ1 (Regulator element associated with dyslexia 1), a regulatory element within DCDC2, is associated with dyslexia. Certain variants of READ1 are related to reading problems. Individuals with such variants are, therefore, more likely to develop dyslexia and language impairment (Powers et al, 2013).
  • DYX3 on chromosome 2p16–p15 (MIM 604254): Linkage analyses in five families have shown the linkage of DYX3 locus (2p15–p16) with dyslexia (Fisher & DeFries, 2002; Kaminen et al, 2003). Unlike DYX2, this locus is not linked to any specific phenotype dimension.
  • DYX4 on chromosome 6q13–q16 (MIM 127700): A susceptible locus DYX4, affecting phonological coding and spelling, has been identified in a large Canadian family on the long arm of chromosome 6q11–q12 (Petryshen et al, 2001).
  • DYX5 on chromosome 3p12–q12 (MIM 606896): In a study of 77 US-American families with speech–sound disorder, which involves impairments in phonological processing, DYX5 was reported to be strongly linked (Stein et al, 2004). In another linkage study carried out in a large Finnish family, chromosome 3p12–q13 was found to be responsible for developmental dyslexia (Nopola-Hemmi et al, 2001). A dominant gene, ROBO1 (roundabout Drosophila homolog of 1), was detected as a likely candidate gene in this region.
  • DYX6 on chromosome 18p11 (MIM 606616): Genome-wide scan on family samples from Oxford and Colorado showed DYX6 on chromosome 18p11 as a quantitative trait locus affecting dyslexia (Fisher et al, 2002). It was associated with multiple aspects of reading ability (Marlow et al, 2003).
  • DYX7 on chromosome 11p15 (MIM 127700): A susceptibility locus, DYX7, containing gene for dopamine D4 receptor (DRD4) on chromosome 11p15.5 was found to be associated with developmental dyslexia (Hsiung et al, 2004).
  • DYX8 on chromosome 1p34–p36 (MIM 608995): Three studies have stated the linkage of DYX8 (1p34–p36) to developmental dyslexia (Rabin et al, 1993; Grigorenko et al, 2001; Tzenova et al, 2004). This region was found to be linked to the phonological aspect of dyslexia (Grigorenko et al, 2001; Tzenova et al, 2004).
  • DYX9 on chromosome Xp27 (MIM 300509): In a genome scan of a Dutch multiplex family with dyslexia, evidence for linkage to dyslexia was observed at Xq27 which harbors DYX9 (de Kovel et al, 2004).

Other linkage regions in dyslexia

Besides HGNC-listed DYX1–DYX9 regions, linkage for word reading on chromosome 13q12 (Igo et al,2006), and for phonological decoding efficiency on chromosome 2q22 have been reported (Raskind et al, 2005). Bivariate linkage scan on families with reading ability and attention deficit/hyperactivity disorder (ADHD) has shown pleiotropic loci on chromosome regions 14q32, 13q32 and 20q11 (Gayan et al, 2005). In addition, evidence of linkage for reading ability in affected sibling pairs with ADHD has been found on chromosome 10q11, 16p12 and 17q22(Loo et al,2004).


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