A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia

Recent application of nonparametric-linkage analysis to reading disability has implicated a putative quantitative-trait locus (QTL) on the short arm of chromosome 6. In the present study, we use QTL methods to evaluate linkage to the 6p25-21.3 region in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. We have assessed linkage directly for several quantitative measures that should correlate with different components of the phenotype, rather than using a single composite measure or employing categorical definitions of subtypes. Our measures include the traditional IQ/reading discrepancy score, as well as tests of word recognition, irregular-word reading, and nonword reading. Pointwise analysis by means of sib-pair trait differences suggests the presence, in 6p21.3, of a QTL influencing multiple components of dyslexia, in particular the reading of irregular words (P=.0016) and nonwords (P=.0024). A complementary statistical approach involving estimation of variance components supports these findings (irregular words, P=.007; nonwords, P=.0004). Multipoint analyses place the QTL within the D6S422-D6S291 interval, with a peak around markers D6S276 and D6S105 consistently identified by approaches based on trait differences (irregular words, P=.00035; nonwords, P=.0035) and variance components (irregular words, P=.007; nonwords, P=.0038). Our findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested. Further studies will be necessary to obtain a more precise localization of this QTL, which may lead to the isolation of one of the genes involved in developmental dyslexia.     

Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23

Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.     

Concomitant chemoradiotherapy for incompletely resected supratentorial low-grade astrocytoma in children: preliminary report

Interval mapping was used to identify putative quantitative trait loci (QTL) for blood pressure and cardiac mass on Chromosome (Chr) 3 in F1(S x R) x S population of 150 rats raised on an 8% NaCl diet. Two genetic markers 95.7 cM apart, D3Wox3 and D3Mco5 (tightly linked to Edn3), showed "suggestive" linkage to blood pressure (LOD = 2.0 and 1.8 respectively). In addition, D3Wox3 showed "suggestive" linkage to heart weight (LOD = 2.5), and D3Mco5 showed "suggestive" linkage to body weight-adjusted heart weight (LOD = 2.1). Congenic rats (designated S.R-Edn3) were constructed by introgressing the R-rat Edn3 allele (and flanking loci) into the S strain. On a 2% NaCl diet, S.R-Edn3 rats had lower blood pressure (21.4 mm Hg, P = 0. 0005) and heart weight (59 mg, P = 0.0038) compared with S rats, confirming the existence of a blood pressure QTL on Chr 3 near Edn3 even though QTL linkage analysis of blood pressure did not achieve stringent statistical criteria for significance. The results of the congenic experiment and the large distance between the two putative QTL suggest the presence of at least two independent blood pressure/cardiac mass QTL detectable on Chr 3 in the Dahl rat model of genetic hypertension.     

The double-deficit hypothesis and difficulties in learning to read a regular orthography.

In 2 large longitudinal studies, we selected 3 subgroups of German-speaking children (phonological awareness deficit, naming-speed deficit, double deficit) at the beginning of school and assessed reading and spelling performance about 3 years later. Quite different from findings with English-speaking children, phonological awareness deficits did not affect phonological coding in word recognition but did affect orthographic spelling and foreign-word reading. Naming-speed deficits did affect reading fluency, orthographic spelling, and foreign-word reading. Apparently, in the context of a regular orthography and a synthetic phonics teaching approach, early phases of literacy acquisition (particularly the acquisition of phonological coding) are less affected by early phonological awareness deficits than by later phases that depend on the build up of orthographic memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Korean-English biliteracy acquisition: Cross-language phonological and orthographic transfer.

Cross-language phonological and orthographic relationship in the biliteracy acquisition of children learning to read Korean and English was investigated in this study. Forty-five Korean-English bilingual children were tested in first-language (L1; Korean) and 2nd-language (L2; English) reading skills focusing on 2 reading processes--phonological and orthographic processing. The authors found that phonological skills in L1 and L2 were strongly correlated, and Korean phonological skills explained a unique amount of variance in English pseudoword reading beyond English phonological and orthographic skills. However, there was limited orthographic skill transfer between the 2 systems. Results are discussed within the framework of universal phonological processes in learning to read. The authors conclude that bilingual reading acquisition may be a joint function of general phonological processes and orthographic-specific skills. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort. METHODS: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds [LOD], 2.15; P = 0.003) for CD and at D12S75 (LOD, 0.92; P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52; P = 0.007). Multipoint support peaked above markers D16S409 and D16S411 (LOD, 1.7). CONCLUSIONS: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.     

On subtypes of developmental dyslexia: Evidence from processing time and accuracy scores.

Determined the proportion of phonological dyslexics (Ph-DYS) and surface dyslexics (S-DYS) in a population of French dyslexics by applying A. Castles and M. Coltheart's (1993) regression method to 2 diagnostic measures: pseudo-word and irregular-word processing time. 31 dyslexics were matched to 19 average readers of the same age (aged 10 yrs, CA controls) and to 19 younger children of the same reading level (aged 8 yrs, RL controls). Compared to CA controls, there were more Ph-DYS than S-DYS. Compared to RL controls, there were still a high number of Ph-DYS. The reliability of these subtypes across different measures of phonological and orthographic skills was also examined. Compared to RL controls, both groups of dyslexics were found to be impaired only in phonological skills. The moment at which the 2 dissociated profiles emerged in the course of cognitive development was assessed by examining data that was collected when the children were 7 and 8 yrs old. The results show that only the S-DYS's orthographic deficit increased with development. The authors also looked at whether the Ph-DYS and S-DYS profiles were associated with other specific cognitive deficits. Specific deficits in phonemic awareness and in phonological short-term memory were found for both Ph-DYS and S-DYS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reading skills in hyperlexia: A developmental perspective.

Hyperlexia is characterized by advanced word-recognition skills in individuals who otherwise have pronounced cognitive, social, and linguistic handicaps. Language, word recognition, and reading-comprehension skills are reviewed to clarify the nature and core deficits associated with the disorder. It is concluded that hyperlexia should be viewed as part of the normal variation in reading skills, which are themselves associated with individual differences in phonological, orthographic, and semantic processing, short-term memory, and print exposure. A compulsive preoccupation with reading may also be crucial to the development of a hyperlexic reading profile. A theoretical framework, based on recent connectionist models of reading development, is described. This perspective provides a satisfactory account for how individual differences in a number of different skills can lead to a variety of manifestations of reading behavior, including hyperlexia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exclusion of BMP6 as a candidate gene for cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia in humans that has been mapped to the short arm of chromosome 6. We report linkage of a CCD mutation to 6p21 in a large family and exclude the bone morphogenetic protein 6 gene (BMP6) as a candidate for the disease by cytogenetic localization and genetic recombination. CCD was linked with a maximal two-point LOD score of 7.22 with marker D6S452 at theta = 0. One relative with a recombination between D6S451 and D6S459 and another individual with a recombination between D6S465 and CCD places the mutation within a 7 cM region between D6S451 and D6S465 at 6p21. A phage P1 genomic clone spanning most of the BMP6 gene hybridized to chromosome 6 in band region p23-p24 using FISH analysis, placing this gene cytogenetically more distal than the region of linkage for CCD. We derived a new polymorphic marker from this same P1 clone and found recombinations between the marker and CCD in this family. The results confirm the map position of CCD on 6p21, further refine the CCD genetic interval by identifying a recombination between D6S451 and D6S459, and exclude BMP6 as a candidate gene.     

Are word-reading processes the same or different in adult literacy students and third–fifth graders matched for reading level?

This study examined whether word-reading processes operate similarly in adult literacy (AL) students and elementary school students matched for reading level. Comparison of mean performances revealed that adults were severely deficient on phonologically complex tasks (segmentation, deletion, and nonword reading). In contrast, on orthographically complex tasks, adults revealed both strengths (sight-word reading) and weaknesses (spelling). Regression analyses revealed that individual differences in word and nonword reading abilities were explained by the same orthographic and phonological processes in AL students and children, despite differences in their levels of performance. Correlations between word reading and spelling measures were weaker among AL students than among children. Inadequate integradon of these skills may explain adults' phonological deficits as well as their reading acquisition difficulties. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Orthographic analogies and early reading: Evidence from a multiple clue word paradigm.

Two experiments using a variation of the clue word analogy task (Goswami, 1986) explored whether children can make orthographic analogies when given multiple clue words, beyond the known effects of purely phonological activation. In Experiment 1, 42 children (mean age 6 years and 8 months) were first taught 3 “clue” words (e.g., fail, mail, jail) and then shown target words sharing orthographic and phonological rimes (e.g., hail), phonological rimes (e.g., veil), orthographic and phonological vowel digraphs (e.g., wait), phonological vowel digraphs (e.g., vein), or unrelated controls (e.g., bard). All word types were advantaged at posttest over unrelated controls. A small additional advantage for orthographic and phonological rimes over phonological rimes was evident in by-participant analysis. Finally, regression analysis showed a specific relationship between onset-rime phonological awareness and orthographic rime clue word task transfer. Experiment 2 replicated Experiment 1 with 30 children (M age = 7 years, 0 months) and added a distinct group of children taught multiple clue words sharing vowel digraphs (e.g., gait, maim, maid). Results showed advantages for all words over unrelated controls and a small additional advantage for orthographic and phonological vowel digraphs over phonological vowel digraphs in the by-participant analysis. Overall, results suggest that some young children do have the ability to make orthographic analogies when given multiple exemplars but that most improvement in target word reading reflects purely phonological activation. Practical steps for identifying genuine analogy use in a subset of children are thus described. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Dysfluent reading in the absence of spelling difficulties: A specific disability in regular orthographies.

Two large studies identified substantial numbers of German-speaking children (Grade 3) with marked dissociations between reading and spelling difficulties. These dissociations were expected because German exhibits high regularity in the direction of graphemes to phonemes (forward regularity) but not in the direction of phonemes to graphemes (backward regularity). High forward regularity allows reliance on phonological processing in reading (even in advanced fluent reading), whereas low backward regularity requires reliance on orthographic memory representations in spelling. Dysfluent reading in the absence of spelling difficulties was associated only with a naming speed deficit--assessed at school entrance--but not with phonological memory or phonological awareness deficits. In contrast, a specific spelling deficit was preceded by phonological deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Structural equation modeling of relationships among developmental skills and writing skills in primary- and intermediate-grade writers.

Used multiple-group structural equation modeling to analyze structural relationships between latent factors underlying writing-related developmental skills and component writing skills in Grades 1–6. For handwriting, both motor skills and orthographic coding contributed to the model fit, but only the path from orthographic coding was significant at all grade levels. For spelling, only the path from orthographic coding was significant in the primary grades, but both that path and the path from phonological coding were significant in the intermediate grades. For compositional quality, both reading and oral language contributed in the primary grades, but the model was unclear in the intermediate grades because of high covariance between those factors. Theoretical and educational implications of the findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A new Graves disease-susceptibility locus maps to chromosome 20q11.2. International Consortium for the Genetics of Autoimmune Thyroid Disease

The autoimmune thyroid diseases (AITDs) include two related disorders, Graves disease (GD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of.3. The maximum nonparametric LOD score was 2.4 (P=.00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major GD-susceptibility gene on chromosome 20q11.2.     

Activation of phonological codes during eye fixations in reading.

Two experiments addressed the issue of whether phonological codes are activated early in a fixation during reading using the fast-priming technique (S. C. Sereno & K. Rayner, 1992). Participants read sentences and, at the beginning of the initial fixation in a target location, a priming letter string was displayed, followed by the target word. Phonological priming was assessed by the difference in the gaze duration on the target word between when the prime was a homophone and when it was a control word equated with the homophone on orthographic similarity to the target. Both experiments demonstrated homophonic priming with prime durations of about 35 ms, but only for high-frequency word primes, indicating that lexicality was guiding the speed of the extraction of phonological codes early in a fixation. Evidence was also obtained for orthographic priming, and the data suggest that orthographic and phonological priming effects interact in a mutually facilitating manner. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Membrane sterol composition modulates the pore forming activity of syringomycin E in human red blood cells

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43.     

Print exposure as a predictor of word reading and reading comprehension in disabled and nondisabled readers.

The relation of print exposure, measured by a revised version of A. E. Cunningham and K. E. Stanovich's (1990) Title Recognition Test (TRT), to word reading and reading comprehension was examined in disabled and nondisabled readers, Grades 5–9. In disabled readers, the TRT was a significant predictor of word reading when phonological skill was accounted for but not when orthographic ability was added to the regression equation, suggesting that the TRT overlaps considerably with orthographic skill. The TRT significantly predicted nondisabled readers' word reading after both phonological and orthographic skills were accounted for. The TRT contributed significantly to reading comprehension once variance was partialed from higher order reading processes for disabled readers only. The TRT's power to predict comprehension may be ascribed to the effects of print exposure on automaticity of word recognition, knowledge, or familiarization with text structure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36

We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The clinical association of sensorineural hearing loss with pili torti (broken, twisted hairs) was described >30 years ago by Bjornstad; subsequently, several small families have been studied. We evaluated a large kindred with Bjornstad syndrome in which eight members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between loci D2S1371 and D2S163. We speculate that intermediate filament and intermediate filament-associated proteins are good candidate genes for causing Bjornstad syndrome.     

Examining the Interactivity of Lexical Orthographic and Phonological Processing.

The number and type of connections involving different levels of orthographic and phonological representations differentiate between several models of spoken and visual word recognition. At the sublexical level of processing, Borowsky, Owen, and Fonos (1999) demonstrated evidence for direct processing connections from grapheme representations to phoneme representations (i.e., a sensitivity effect) over and above any bias effects, but not in the reverse direction. Neural network models of visual word recognition implement an orthography to phonology processing route that involves the same connections for processing sublexical and lexical information, and thus a similar pattern of cross-modal effects for lexical stimuli are expected by models that implement this single type of connection (i.e., orthographic lexical processing should directly affect phonological lexical processing, but not in the reverse direction). Furthermore, several models of spoken word perception predict that there should be no direct connections between orthographic representations and phonological representations, regardless of whether the connections are sublexical or lexical... (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treating the core deficits of developmental dyslexia: Evidence of transfer of learning after phonologically- and strategy-based reading training programs.

Individuals with dyslexia have difficulty generalizing from word identification training. This study compared 2 forms of word identification training to promote transfer of learning by children with dyslexia. 62 children were randomly assigned to 1 of the training programs or to a study skills control program. One program trained phonological analysis and blending skills and provided direct instruction of letter–sound correspondences; the other trained the acquisition, use, and monitoring of 4 metacognitive decoding strategies. Results provided clear evidence of transfer of learning after treatment of the core reading deficits of these children. Both training approaches were associated with large positive effects, transfer on several measures, and generalized achievement gains. The phonological program resulted in greater generalized gains in the phonological domain and the strategy program in broader-based transfer for real words. (PsycINFO Database Record (c) 2010 APA, all rights reserved)