Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK [Letter to JMG]

Developmental dyslexia is diagnosed as a specific impairment in reading ability, despite adequate intelligence and educational opportunity,1 that affects approximately 5% of schoolchildren.2 Much evidence has been accumulated from twin and family based studies to indicate that dyslexia can have a hereditary basis, but that the genetic aetiology is complex, involving multiple risk factors.1–3 Linkage analysis has identified numerous genomic regions that may harbour susceptibility genes influencing dyslexia, including on chromosomes 1, 2, 3, 6, 15, and 18, with varying degrees of reproducibility.1,2 The first of these linkages was reported two decades ago,4 to the centromere of chromosome 15. Although subsequent studies failed to replicate linkage to this specific region,5 there is evidence for linkage elsewhere on chromosome 15, particularly at 15q21 ( DYX1 , OMIM 127700).6,7 Recently, DYX1C1 (also known as EKN1 ) was proposed as the gene underlying the putative effect on 15q21.8 This was initially based on studies of a balanced translocation, t(2;15)(q11;q21), co-segregating with reading problems within a single nuclear family from Finland.9 The 15q21 breakpoint in this family directly disrupts DYX1C1 , in an interval that includes exons 8 and 9 (fig 1). Investigation of DYX1C1 in individuals from 20 additional Finnish families with multiple cases of dyslexia led to the identification of eight single nucleotide polymorphisms (SNPs). Two of these SNPs were found to associate with dyslexia in these families, and in additional Finnish affected cases and controls. It was proposed that these two associated SNPs altered the expression or function of DYX1C1 , one by altering a transcription factor binding site, the other as a result of a premature truncation of the protein product by four amino acids, thereby leading to increased risk of developing dyslexia.8 Figure 1 Location of DYX1C1 on chromosome 15. Top: …