No abstract

Context: Dyslexia is a common disorder with a strong genetic component, but despite significant research effort, the aetiology is still largely unknown. Objective: To identify loci contributing to dyslexia risk. Methods: This was a genomewide linkage analysis in a single large family. Dutch families with at least two first degree relatives suffering from dyslexia participated in the study. Participants were recruited through an advertisement campaign in papers and magazines. The main outcome measure was linkage between genetic markers and dyslexia phenotype. Results: Using parametric linkage analysis, we found strong evidence for a locus influencing dyslexia on Xq27.3 (multipoint lod = 3.68). Recombinations in two family members flanked an 8 cM region, comprising 11 currently confirmed genes. All four males carrying the risk haplotype had very low scores on the reading tests. The presentation in females was more variable, but 8/9 females carrying the risk haplotype were diagnosed dyslexic by our composite score, so we considered the putative risk allele to be dominant with reduced penetrance. Linkage was not found in an additional collection of affected sibling pairs. Conclusions: A locus influencing dyslexia risk is probably located between markers DXS1227 and DXS8091 on the X chromosome, closely situated to a locus indicated by a published genome scan of English sibling pairs. Although the locus may not be a common cause for dyslexia, the relatively small and gene poor region offers hope to identify the responsible gene.

ADHD is a neuropsychiatric disorder characterized by chronic hyperactivity, inattention and impulsivity, which affects about 5% of school-age children. ADHD persists into adulthood in at least 15% of cases. It is highly heritable and familial influences seem strongest for ADHD persisting into adulthood. However, most of the genetic research in ADHD has been carried out in children with the disorder. The gene that has received most attention in ADHD genetics is SLC6A3/DAT1 encoding the dopamine transporter. In the current study we attempted to replicate in adults with ADHD the reported association of a 10-6 SLC6A3-haplotype, formed by the 10-repeat allele of the variable number of tandem repeat (VNTR) polymorphism in the 3 0 untranslated region of the gene and the 6-repeat allele of the VNTR in intron 8 of the gene, with childhood ADHD. In addition, we wished to explore the role of a recently described VNTR in intron 3 of the gene. Two hundred sixteen patients and 528 controls were included in the study. We found a 9-6 SLC6A3-haplotype, rather than the 10-6 haplotype, to be associated with ADHD in adults. The intron 3 VNTR showed no association with adult ADHD. Our findings converge with earlier reports and suggest that age is an important factor to be taken into account when assessing the association of SLC6A3 with ADHD. If confirmed in other studies, the differential association of the gene with ADHD in children and in adults might imply that SLC6A3 plays a role in modulating the ADHD phenotype, rather than causing it.

Background: During this presentation, the first pharmacogenetic study on response to methylphenidate (MPH) in adults with ADHD will be reported. Methods: We performed a stratified analysis of the association between response to MPH, assessed under double-blind conditions, in 42 adults with ADHD, and polymorphisms in the genes encoding the dopamine transporter, SLC6A3 (DAT1), the norepinephrine transporter, SLC6A2 (NET), and the dopamine receptor D4, DRD4. Results: Polymorphisms in the DRD4 and the SLC6A2 (NET) genes were not significantly associated with the response to MPH treatment; however, the VNTR polymorphism in the 3'untranslated region of SLC6A3 (DAT1) was significantly associated with an increased likelihood of a response to MPH treatment (odds ratio 5.4; 95% CI 1.4-21.9) in heterozygous 10-repeat allele carriers in comparison with the 10/10 homozygotes: 52.2% of the participants heterozygous for the 10-repeat allele improved significantly on MPH treatment whereas only 22.2% of the 10/10 homozygous individuals did. Conclusions: This study confirms that the SLC6A3 (DAT1) genotype may have an influential role in determining the response to MPH in the treatment of ADHD. The SLC6A3 (DAT1) gene might be a factor worth evaluating further in the future regarding choice of treatment and possibly dose adjustment.

Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1-25.3 flanked by the polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at theta=0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the -3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.