Approximately 3-10% of people have specific difficulties in reading, despite adequate intelligence, education, and social environment. We report here the characterization of a gene, DYX1C1 near the DYX1 locus in chromosome 15q21, that is disrupted by a translocation t(2;15)(q11;q21) segregating coincidentally with dyslexia. Two sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (؊3G 3 A) and a codon (1249G 3 T), introducing a premature stop codon and truncating the predicted protein by 4 aa, associate alone and in combination with dyslexia. DYX1C1 encodes a 420-aa protein with three tetratricopeptide repeat (TPR) domains, thought to be protein interaction modules, but otherwise with no homology to known proteins. The mouse Dyx1c1 protein is 78% identical to the human protein, and the nonhuman primates differ at 0.5-1.4% of residues. DYX1C1 is expressed in several tissues, including the brain, and the protein resides in the nucleus. In human brain, DYX1C1 protein localizes to a fraction of cortical neurons and white matter glial cells. We conclude that DYX1C1 should be regarded as a candidate gene for developmental dyslexia. Detailed study of its function may open a path to understanding a complex process of development and maturation of the human brain.

Developmental dyslexia is a neurofunctional disorder characterised by an unexpected diYculty in learning to read and write despite adequate intelligence, motivation, and education. Previous studies have suggested mostly quantitative susceptibility loci for dyslexia on chromosomes 1, 2, 6, and 15, but no genes have been identified yet. We studied a large pedigree, ascertained from 140 families considered, segregating pronounced dyslexia in an autosomal dominant fashion. AVected status and the subtype of dyslexia were determined by neuropsychological tests. A genome scan with 320 markers showed a novel dominant locus linked to dyslexia in the pericentromeric region of chromosome 3 with a multipoint lod score of 3.84. Nineteen out of 21 aVected pedigree members shared this region identical by descent (corrected p<0.001). Previously implicated genomic regions showed no evidence for linkage. Sequencing of two positional candidate genes, 5HT1F and DRD3, did not support their role in dyslexia. The new locus on chromosome 3 is associated with deficits in all three essential components involved in the reading process, namely phonological awareness, rapid naming, and verbal short term memory. (J Med Genet 2001;38:658-664)

Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a nonparametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets. D evelopmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, environment, and normal senses. The impairment in dyslexia appears to be in phonological processing, which interferes with the function of the linguistic system at the higher level, such as semantics.1 Functional brain imaging studies have shown that dyslectic subjects have a common neuroanatomical basis.2 Dyslexia is relatively common affecting 5-10% of the population depending on the definition.3 Previous twin and family studies have established a large genetic component in the aetiology of dyslexia. 4 Although at least two loci have shown clearly dominant transmission (DYX3 and DYX5), the mode of inheritance seems to be non-Mendelian for other loci. Therefore, the aetiology of dyslexia is likely to be heterogeneous 5 and at least five loci have consistently been linked to dyslexia: DYX1 on 15q21, DYX2 on 6p21.3, DYX3 on 2p16-p15, DYX5 on 3p12-q13, and DYX6 on 18p11.2 (http//www.ncbi.nlm.nih.gov/omim).The first gene associated with speech and language development, FOXP2 (forkhead box P2) on 7q31, was identified through a large pedigree, the KE family, with half of the family members affected by a severe speech and language disorder (SPCH1). 6 They have mainly problems in articulation, expressive speech, and grammar, but also impairment in phonological processing is detected.7 8 All affected subjects have a G to A nucleotide transition in exon 14 of FOXP2. In addition, an unrelated subject with a similar phenotype has a de novo balanced reciprocal translocation t(5;7)(q22;q31.2) mapping specifically to an intron between exons 3b and 4 of FOXP2. 9The FOXP2 ...