Dyslexia and DYX1C1: deficits in reading and spelling associated with a missense mutation

Abstract

The status of DYX1C1 (C15q21.3) as a susceptibility gene for dyslexia is unclear. We report the association of this gene with reading and spelling ability in a sample of adolescent twins and their siblings. Family-based association analyses were carried out on 13 single-nucleotide polymorphisms (SNPs) in DYX1C1, typed in 790 families with up to 5 offspring and tested on 6 validated measures of lexical processing (irregular word) and grapheme-phoneme decoding (pseudo-word) reading-and spelling-based measures of dyslexia, as well as a short-term memory measure. Significant association was observed at the misssense mutation rs17819126 for all reading measures and for spelling of lexical processing words, and at rs3743204 for both irregular and nonword reading. Verbal short-term memory was associated with rs685935. Support for association was not found at rs3743205 and rs61761345 as previously reported by Taipale et al., but these SNPs had very low (0.002 for rs3743205) minor allele frequencies in this sample. These results suggest that DYX1C1 influences reading and spelling ability with additional effects on short-term information storage or rehearsal. Missense mutation rs17819126 is a potential functional basis for the association of DYX1C1 with dyslexia.

Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort

“…It is possible that this gene represents a genuine dyslexia risk gene and that common risk variants in DYX1C1 are contributing to the phenotype, as supported also by associations with reading and spelling in an unselected adolescent cohort from Australia. 15 However, it might be also possible that high-penetrance mutations in DYX1C1 or in the other dyslexia candidate genes are only present in some familial cases. In this case, a deep-sequencing approach in families with dyslexia would be more appropriate to find an enrichment of such highpenetrance private mutations.…”

“…DYX1C1 has also been associated with reading and spelling ability in a large unselected group of adolescents from Australia. 15 Furthermore, it has been shown that dyslexia-associated variants within the promoter region of DYX1C1 16 influence the binding affinity of transcription factor complexes. 17 Two genes have been reported to be associated with dyslexia within the linkage region on chromosome 6p22.2: DCDC2 (doublecortin domain-containing protein 2, MIM 605755) [18][19][20] and KIAA0319 (MIM 609269).…”

A family‐based association analysis and meta‐analysis of the reading disabilities candidate gene DYX1C1

“…Two independent Australian cohort studies also performed quantitative analyses of reading and reading related measures in population-based samples [Bates et al, 2010;Paracchini et al, 2011]. Bates et al [2010] found three SNPs that were significantly associated with different measures: rs685935 with short-term memory; rs17819126 with irregular reading, nonword reading, and irregular spelling; and rs3743204 with nonword reading. Paracchini et al [2011] found that spelling was associated with the three markers rs7174102, rs8043049, and rs8037376, and reading associated with rs8040756.…”

“…Other studies did not find association between DYX1C1 SNPs and quantitative reading tasks [Scerri et al, 2004;Meng et al, 2005]. Two independent Australian cohort studies also performed quantitative analyses of reading and reading related measures in population-based samples [Bates et al, 2010;Paracchini et al, 2011]. Bates et al [2010] found three SNPs that were significantly associated with different measures: rs685935 with short-term memory; rs17819126 with irregular reading, nonword reading, and irregular spelling; and rs3743204 with nonword reading.…”

“…The markers rs600753 and rs16787 were previously found to be significant in several combinations of haplotypes [Dahdouh et al, 2009]. The rs1789126 marker was selected because of a positive association in an Australian sample [Bates et al, 2010], and the rs1289331 was selected as it was suggested to be the binding site of the SP1 transcription factor [Tapia-Paez et al, 2008].…”