LETTER TO JMG A locus on 15q15-15qter influences dyslexia: further support from a transmission/disequilibrium study in an Italian speaking population

D evelopmental dyslexia (dyslexia) is a heritable condition typically diagnosed in the first school years, characterised by an impairment of reading abilities in spite of normal intelligence and adequate educational opportunities. While the exact neurobiological mechanisms underlying this condition remain obscure, the most convincing current aetiopathogenetic view of dyslexia is that impaired reading stems from a defective representation and manipulation of phonemes, —that is, the sounds that we combine to build words. There are at least two major complications when studying the ultimate causes of dyslexia. Firstly, the composite neuropsychological picture that often marks dyslexia may lead people to consider reading problems as a part of a more extended neurobiological syndrome whose phenotypic boundaries are blurred, and whose genetic determinants may be especially difficult to identify with certainty. Secondly, the leading criterion to diagnose dyslexia remains that of a reading performance below the population mean (typically, a reading score two standard deviations below the general population mean). While reading performance is distributed normally in the population, the prevalence of dyslexics will vary considerably across different cultures, because it depends on the complexity of orthographic rules specific to a given language to which a subject is exposed. Contradicting a culturally bound identity of dyslexia is a recent, functional brain imaging study of adult subjects with dyslexia from different cultures and languages (English, French, Italian) that showed the same abnormal patterns of brain activation during implicit and explicit reading. This suggests common neurobiological causes for dyslexia regardless of a person’s spoken language, while variation in prevalence estimates across different cultures could at least partially reflect local difficulties specific to each language, when homogenous diagnostic criteria are applied. While functional brain imaging findings suggest biological unity for dyslexia, evidence based on genetic analyses of common determinants of dyslexia in spite of markedly different orthographies and languages is incomplete. The evidence that dyslexia has a genetic basis is, nonetheless, very convincing. The tendency of dyslexia to run in families has become clear since its earliest descriptions, and modern family studies indicate that a substantial majority of affected children have affected relatives, the average risk among first degree relatives being about 30%. Twin studies show that the role of genetic factors outweighs that of shared, non-genetic factors in explaining such familial resemblance for dyslexia. The complexity of the dyslexia phenotype has been taken into account by some, but not all, genetic studies. Estimates of broad heritability in twin samples vary quite widely across specific phenotypic components of dyslexia, yielding estimates that range between 0.44 and 0.75. Likewise, molecular genetic studies have investigated dyslexia both as a categorically defined, putatively homogenous illness, and as a composite condition, through specific and putatively independent components of phenotype with a wide array of strategies, including parametric and model free linkage analyses, as well as family based association designs. Overall, promising findings have been obtained for regions on chromosomes 1, 9 2, 3, 6p, 6q, 15q, 23–28 and 18. Robust results have come from molecular genetic research studies of dyslexia on chromosome 15. These were prompted by an initial evidence of a 3.24 lod score in a parametric linkage study of chromosome 15 in three generational pedigrees segregating dyslexia, which used heteromorphisms of the centromere region as markers. These results, however, were not confirmed by two similar, successive studies. 30 In a more recent study Smith et al replicated their earlier finding with markers within the 15q15-15qter region, using both a quantitative and qualitative phenotype definition of dyslexia, and a non-parametric approach (the Haseman-Elston regression model). Linkage within the 15q15-15qter region was further confirmed in a non-parametric analysis using the De Fries Fulker regression approach and a quantitative definition of dyslexia. Grigorenko et al found a lod score of 3.15 in single point linkage parametric analysis between the microsatellite D15S143 and a ‘‘single–word reading’’ component of reading performance. In the same study, non-parametric analyses generally yielded negative results. Defining a phenotype of spelling disability, other authors found linkage with markers