Increased variability of stimulus-driven cortical responses is associated with genetic variability in children with and without dyslexia.

Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Compliance With Evidence-Based Guidelines and Interhospital Variation in Mortality for Patients With Severe Traumatic Brain Injury.

IMPORTANCE: Compliance with evidence-based guidelines in traumatic brain injury (TBI) has been proposed as a marker of hospital quality. However, the association between hospital-level compliance rates and risk-adjusted clinical outcomes for patients with TBI remains poorly understood. OBJECTIVE: To examine whether hospital-level compliance with the Brain Trauma Foundation guidelines for intracranial pressure monitoring and craniotomy is associated with risk-adjusted mortality rates for patients with severe TBI. DESIGN, SETTING, AND PARTICIPANTS: All adult patients (N = 734) who presented to a regional consortium of 14 hospitals from January 1, 2009, through December 31, 2010, with severe TBI (ie, blunt head trauma, Glasgow Coma Scale score of <9, and abnormal intracranial findings from computed tomography of the head). Data analysis took place from December 2013 through January 2015. We used hierarchical mixed-effects models to assess the association between hospital-level compliance with Brain Trauma Foundation guidelines and mortality rates after adjusting for patient-level demographics, severity of trauma (eg, mechanism of injury and Injury Severity Score), and TBI-specific variables (eg, cranial nerve reflexes and findings from computed tomography of the head). MAIN OUTCOMES AND MEASURES: Hospital-level risk-adjusted inpatient mortality rate and hospital-level compliance with Brain Trauma Foundation guidelines for intracranial pressure monitoring and craniotomy. RESULTS: Unadjusted mortality rates varied by site from 20.0% to 50.0% (median, 42.6; interquartile range, 35.5-46.2); risk-adjusted rates varied from 24.3% to 56.7% (median, 41.1; interquartile range, 36.4-47.8). Overall, only 338 of 734 patients (46.1%) with an appropriate indication underwent placement of an intracranial pressure monitor and only 134 of 335 (45.6%) underwent craniotomy. Hospital-level compliance ranged from 9.6% to 65.2% for intracranial pressure monitoring and 6.7% to 76.2% for craniotomy. Despite widespread variation in compliance across hospitals, we found no association between hospital-level compliance rates and risk-adjusted patient outcomes (Spearman ρ = 0.030 [P = .92] for ICP monitoring and Spearman ρ = -0.066 [P = .83] for craniotomy). CONCLUSIONS AND RELEVANCE: Hospital-level compliance with evidence-based guidelines has minimal association with risk-adjusted outcomes in patients with severe TBI. Our results suggest that caution should be taken before using compliance with these measures as independent quality metrics. Given the complexity of TBI care, outcomes-based metrics, including functional recovery, may be more accurate than current process measures at determining hospital quality.

The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains.

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated.

Intracranial pressure monitoring and inpatient mortality in severe traumatic brain injury: A propensity score-matched analysis.

BACKGROUND: Although intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI) is recommended by the Brain Trauma Foundation, the benefits remain controversial. We sought to determine the impact of ICP monitor placement on inpatient mortality within a regional trauma system after correcting for selection bias through propensity score matching. METHODS: Data were collected on all severe TBI cases presenting to 14 trauma centers during the 2-year study period (2009-2010). Inclusion criteria were as follows: blunt injury, Glasgow Coma Scale (GCS) score of 8 or lower in the emergency department, and abnormal intracranial findings on head computed tomography (CT). Two separate multivariate logistic regression models were used to predict ICP monitor placement and inpatient mortality after controlling for demographics, severity of injury, comorbidities, and TBI-specific variables (GCS score, pupil reactivity, international normalized ratio, and nine specific head CT findings). To account for selection bias, we developed a propensity score-matched model to estimate the "true" effect of ICP monitoring on in-hospital mortality. RESULT: A total of 844 patients met inclusion criteria; 22 died on arrival to the emergency department. Inpatient mortality was 38.8%; 46.0% of the patients underwent ICP monitor placement. Unadjusted mortality rates were significantly lower in the ICP monitoring group (30.7% vs. 45.7%, p < 0.001). ICP monitor placement was positively associated with CT findings of subdural hematoma, intraparenchymal contusion, and mass effect and negatively associated with age, alcoholism, and elevated international normalized ratio. After adjusting for selection bias via propensity score matching, ICP monitor placement was associated with an 8.3 percentage point reduction in the risk-adjusted mortality rate. CONCLUSION: ICP monitor placement occurred in only 46% of eligible patients but was associated with significantly decreased mortality after adjusting for baseline risk profile and the propensity to undergo monitoring. As the individual impact of ICP monitoring may vary, future efforts must determine who stands to benefit from invasive monitoring techniques. LEVEL OF EVIDENCE: Therapeutic/care management study, level III.

Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children.

The neuregulin-1 (NRG1) gene is one of the best-validated risk genes for schizophrenia, and psychotic and bipolar disorders. The rs6994992 variant in the NRG1 promoter (SNP8NRG243177) is associated with altered frontal and temporal brain macrostructures and/or altered white matter density and integrity in schizophrenic adults, as well as healthy adults and neonates. However, the ages when these changes begin and whether neuroimaging phenotypes are associated with cognitive performance are not fully understood. Therefore, we investigated the association of the rs6994992 variant on developmental trajectories of brain macro- and microstructures, and their relationship with cognitive performance. A total of 972 healthy children aged 3-20 years had the genotype available for the NRG1-rs6994992 variant, and were evaluated with magnetic resonance imaging (MRI) and neuropsychological tests. Age-by-NRG1-rs6994992 interactions and genotype effects were assessed using a general additive model regression methodology, covaried for scanner type, socioeconomic status, sex and genetic ancestry factors. Compared with the C-carriers, children with the TT-risk-alleles had subtle microscopic and macroscopic changes in brain development that emerge or reverse during adolescence, a period when many psychiatric disorders are manifested. TT-children at late adolescence showed a lower age-dependent forniceal volume and lower fractional anisotropy; however, both measures were associated with better episodic memory performance. To our knowledge, we provide the first multimodal imaging evidence that genetic variation in NRG1 is associated with age-related changes on brain development during typical childhood and adolescence, and delineated the altered patterns of development in multiple brain regions in children with the T-risk allele(s).

Genome-wide association study of shared components of reading disability and language impairment.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

Genetic influences of cortical gray matter in language-related regions in healthy controls and schizophrenia.

Individuals with schizophrenia show a broad range of language impairments, including reading difficulties. A recent structural MRI (sMRI) study linked these difficulties to structural abnormalities in language-related regions (Leonard et al., 2008). Similar regions have been implicated in primary reading disability (RD). Major hypotheses of RD implicate abnormal embryonic neuronal migration in the cortex, and genetic linkage and association studies have identified a number of candidate RD genes that are associated with neuronal migration (Paracchini et al., 2007). Interestingly, evidence suggests at least some individuals with schizophrenia also show impaired neuronal migration in the cortex (Akbarian et al., 1996). Thus the aim of this study was to examine the link between RD-related genes and gray matter volumes in healthy controls and schizophrenia. We used parallel independent component analysis (parallel-ICA) to examine the relationship between gray matter volumes extracted using voxel-based morphometry (VBM) and 16 single nucleotide polymorphisms (SNPs) spanning FOXP2 and four RD-related genes, DCDC2, DYX1C1, KIAA0319 and TTRAP. Parallel-ICA identified five sMRI-SNP relationships. Superior and inferior cerebellar networks were related to DYX1C1 and DCDC2/KIAA0319 respectively in both groups. The superior prefrontal, temporal and occipital networks were positively related to DCDC2 in the schizophrenia, but not the control group. The identified networks closely correspond to the known distribution of language processes in the cortex. Thus, reading and language difficulties in schizophrenia may be related to distributed cortical structural abnormalities associated with RD-related genes.

Decompressive craniectomy: surgical control of traumatic intracranial hypertension may improve outcome.

INTRODUCTION: The purpose of this study was to assess the role of decompressive craniectomy (DC) inpatients with post-traumatic intractable intracranial hypertension (ICH) in the absence of an evacuable intracerebral haemorrhage. METHODS: Retrospective study at LAC+USC Medical Centre including patients who underwent DC for post-traumatic malignant brain swelling or ICH without space occupying haemorrhage, during the period 01/2004 to 12/2008. The analysis included the effect of DC on intracranial pressure (ICP) and timing of DC on functional outcomes and survival. RESULTS: Of 106 patients who underwent DC, 43 patients met inclusion criteria. Of those, 34 were operated within the first 24 h from admission. DC decreased the ICP significantly from 37.8 ± 12.1 mmHg to 12.7 ± 8.2 mmHg in survivors and from 52.8 ± 13.0 to 32.0 ± 17.3 mmHg in non-survivors. Overall 25.6%died (11 of 43), and 32.5% (14 of 43) remained in vegetative state or were severely disabled. Favourable outcome (Glasgow Outcome Scale 4 and 5) was observed in 41.9% (18 of 43). No tendency towards either increased or decreased incidence in favourable outcome was found relative to the time from admission to DC.Six of the 18 patients (33.3%) with favourable outcome were operated on within the first 6 h. CONCLUSIONS: DC lowers ICP and raises CPP to high normal levels in survivors compared to non-survivors.The timing of DC showed no clear trend, for either good neurological outcome or death. Overall, the survival rate of 74.4% is promising and 41.9% had favourable neurological outcome.

Toll-like receptor expression and function in subsets of human gammadelta T lymphocytes.

Two subsets of human gammadelta T cells can be identified by T cell receptor (TCR) V gene usage. Vdelta2Vgamma9 T cells dominate in peripheral blood and recognize microbe- or tumour-derived phosphoantigens. Vdelta1 T cells are abundant in mucosal tissue and recognize stress-induced MHC-related molecules. Toll-like receptors (TLRs) are known to co-stimulate interferon-gamma (IFN-gamma) production in peripheral blood gammadelta T cells and in Vdelta2Vgamma9 T cell lines. By microarray analysis, we have identified a range of genes differentially regulated in freshly isolated gammadelta T cells by TCR versus TCR plus TLR3 stimulation. Furthermore, we have investigated TLR expression in freshly isolated Vdelta1 and Vdelta2 subsets and cytokine/chemokine production in response to TLR1/2/6, 3 and 5 ligands. TLR1,2,6,7 RNA was abundantly expressed in both subsets, whereas TLR3 RNA was present at low levels, and TLR5 and 8 RNA only marginally in both subsets. Despite abundant RNA expression, TLR1 was rarely detectable by flow cytometry. In contrast, TLR2 and TLR6 proteins were detected in purified Vdelta1 and Vdelta2 T cells, and TLR3 protein was detected intracellularly in both subsets. TLR1/2/6, 3 and 5 ligands co-stimulated the IFN-gamma and chemokine secretion in TCR-activated Vdelta1 and Vdelta2 subsets, although the levels of IFN-gamma secreted by Vdelta1 T cells were much lower than those produced by Vdelta2 T cells. Our results reveal comparable expression of TLRs and functional responses to TLR ligands in freshly isolated Vdelta1 and Vdelta2 T cells and underscore the intrinsically different capacity for IFN-gamma secretion of Vdelta1 versus Vdelta2 T cells.

Hemodynamic and oxygen transport patterns after head trauma and brain death: implications for management of the organ donor.

OBJECTIVES: The aims of the present study were to describe the temporal hemodynamic and oxygen transport patterns of patients with head injuries as well as the patterns of those who became brain dead to better understand the role of underlying central regulatory hemodynamic mechanisms and ultimately to improve rates of organ donation. METHODS: We studied 388 consecutive noninvasively monitored patients with severe head trauma; 79 of these became brain dead. Monitoring was started shortly after admission to the emergency department and was designed to describe the sequence of cardiac, pulmonary, and tissue perfusion functions by cardiac index (CI), mean arterial pressure, heart rate, arterial saturation by pulse oximetry (Sapo2), and transcutaneous oxygen and carbon dioxide (Ptco2/Fio2 and Ptcco2) patterns. The latter were used as markers of tissue perfusion or oxygenation. RESULTS: Patients with head injuries who subsequently became brain dead initially had low CI with poor tissue perfusion beginning shortly after emergency department admission. This was followed by a prolonged period characterized by high CI (4.43 +/- 1.3 L x min(-1) x m2) and enhanced tissue oxygenation (Ptco2/Fio2 238 +/- 186). In the late or end stage of brain death, hemodynamic deterioration and collapse led rapidly to arrest. In attempts to maintain hemodynamic stability for organ donation, the effects of various therapies on the hemodynamic patterns were preliminarily described. CONCLUSIONS: The hyperdynamic state with exaggerated peripheral tissue perfusion or oxygenation in brain-dead patients associated with loss of central vasoconstrictive mechanisms of the stress response resulted in unopposed peripheral metabolic vasodilatation producing high CI and tissue perfusion.

Survival, hemodynamics, and tissue oxygenation after head trauma.

BACKGROUND: The aims of this study were to describe the early time course of hemodynamic and tissue perfusion and oxygenation patterns in survivors and nonsurvivors after head injury; to suggest physiologic mechanisms responsible for the observed patterns; and to evaluate postinjury parameters that might be useful for treatment. The hypothesis was that reduced hemodynamics and tissue oxygenation and reduced arterial oxygen saturation affect outcomes. STUDY DESIGN: Sixty patients with head trauma were noninvasively monitored on arrival in the emergency department to assess the temporal hemodynamic patterns associated with head injury; patients who were brain dead were excluded because they have very different hemodynamic patterns. Cardiac index, mean arterial pressure, and heart rate were monitored to assess cardiac function, pulse oximetry to reflect changes in pulmonary function, and transcutaneous oxygen and carbon dioxide to reflect tissue perfusion function. Patients were stratified by inhospital survival outcomes, the Glasgow Coma Scale, and the presence or absence of associated somatic injuries. RESULTS: When all head injured patients were considered together, the predominant findings were high cardiac index, hypertension, mild tachycardia, normal pulmonary function, and reduced tissue oxygenation. The subset of survivors and those with high Glasgow Coma Scale had greater than normal cardiac index responses (4.02 +/- 0.01 (SEM) L/min/m2, p < 0.01 versus normal) and better tissue oxygenation (217 +/- 2 mmHg PtcO2/FiO2) than nonsurvivors (70 +/- 3 mmHg, p < 0.01) and those with low Glasgow Coma Scale (160 +/- 2, p < 0.05). Patterns of patients with associated somatic injuries were similar to those with isolated head injury. CONCLUSIONS: The study suggested that survivors' cardiac index, tissue oxygenation, and arterial oxygen saturation may be considered as markers of resuscitation. Nonsurvivors of head injury had normal blood flow with reduced tissue oxygenation that might have contributed to unfavorable outcomes.

Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.

Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.

Minimally invasive lateral mass screws in the treatment of cervical facet dislocations: technical note.

OBJECTIVE: The technique of lateral mass screw and rod or plate fixation is a major advancement in the posterior instrumentation of the cervical spine. This technique provides rigid three-dimensional fixation, restores the dorsal tension band, and provides highly effective stabilization in patients with many types of traumatic injuries. METHODS: Patient 1 was a 32-year-old man who had been in a motor vehicle accident. He presented with right C5 radiculopathy. X-ray findings included 45% anterolisthesis of C4 on C5, bilateral facet disruption, and right unilateral C4-C5 facet fracture and dislocation. The patient was placed in Gardner-Wells tongs, and the fracture was reduced with 25 pounds of traction. Patient 2 was a 56-year-old woman who had been in a motor vehicle accident that resulted in complete quadriplegia. Her initial imaging studies revealed a C3-C4 right unilateral facet fracture with subluxation. She was placed in traction, and her neurological status was reassessed. The findings of her neurological examination revealed improvement: she was found to have Brown-Séquard syndrome. Patient 3 was a 33-year-old man who was involved in a diving accident that resulted in bilaterally jumped facets at C3-C4. The patient was neurologically intact, and attempts at closed reduction were not successful. RESULTS: Patients 1 and 2 underwent anterior cervical discectomy with iliac crest autograft fusion and plating. They were then placed in the prone position, and a dilator tubular retractor system was used to access the facet joint at the level of interest. The facet joints were then denuded and packed with autograft. Lateral mass screws were then placed by means of the Magerl technique, and a rod was used to connect the top-loading screws. Patient 3 underwent posterior surgery that included only removal of the superior facet, intraoperative reduction, and bilateral lateral mass screw and rod placement. CONCLUSION: This technical note describes the successful placement of lateral mass screw and rod constructs with the use of a minimally invasive approach by means of a tubular dilator retractor system. This approach preserves the integrity of the muscles and ligaments that maintain the posterior tension band of the cervical spine.

Brain death documentation: analysis and issues.

OBJECTIVE: Specific guidelines for documenting the complete loss of brain function, for the declaration of brain death, have been established for 3 decades. This study assessed the quality and completeness of brain death notes and the effects of delays between notes on organ procurement. METHODS: A retrospective review of brain death declarations at a major medical center was performed. Fifty-eight cases, with a total of 121 brain death notes, were identified in a 12-month period. Notes were assessed for clinical and confirmatory tests of brain and brainstem function. Adverse physiological events that occurred in the time intervals between notes were also identified. RESULTS: The clinical tests most likely to be documented were tests of pupillary (86%) and gag (78%) reflexes. Corneal reflexes were tested in only 57% of cases, and motor responses were noted in only 66%. Documentation by the neurosurgery department was generally more complete. The delays between brain death declarations were highly variable but did not result in any loss of donor organs because of hemodynamic derangements. CONCLUSION: To meet the needs of organ recipients and donor families and to comply with hospital, legal, and legislative mandates, hospitals may need to increase quality assurance activities with respect to declarations of brain death. Increased physician education should improve awareness of uniform brain death declaration guidelines.

Polymorphisms in the gene encoding thymus-specific serine protease in the extended HLA complex: a potential candidate gene for autoimmune and HLA-associated diseases.

Positive selection plays a role, together with negative selection, in the prevention of autoimmunity. Thymus-specific serine protease is highly expressed in the thymus and is believed to be involved in positive selection of T cells. The gene encoding thymus-specific serine protease (PRSS16) maps to the extended HLA complex, which harbours several genes predisposing for autoimmune diseases. Here we report the results of scanning the genetic region containing PRSS16 for polymorphisms. Twenty-two polymorphisms were identified, including one missense polymorphism, one deletion leading to elimination of five amino acids, as well as several SNPs in the promoter region.

Evidence for linkage and association with reading disability on 6p21.3-22.

Reading disability (RD), or dyslexia, is a common heterogeneous syndrome with a large genetic component. Several studies have consistently found evidence for a quantitative-trait locus (QTL) within the 17 Mb (14.9 cM) that span D6S109 and D6S291 on chromosome 6p21.3-22. To characterize further linkage to the QTL, to define more accurately the location and the effect size, and to identify a peak of association, we performed Haseman-Elston and DeFries-Fulker linkage analyses, as well as transmission/disequilibrium, total-association, and variance-components analyses, on 11 quantitative reading and language phenotypes. One hundred four families with RD were genotyped with a new panel of 29 markers that spans 9 Mb of this region. Linkage results varied widely in degree of statistical significance for the different linkage tests, but multipoint analysis suggested a peak near D6S461. The average 6p QTL heritability for the 11 reading and language phenotypes was 0.27, with a maximum of 0.66 for orthographic choice. Consistent with the region of linkage described by these studies and others, there was a peak of transmission disequilibrium with a QTL centered at JA04 (chi2=9.48; empirical P=.0033; orthographic choice), and there was strong evidence for total association at this same marker (chi2=11.49; P=.0007; orthographic choice). Although the boundaries of the peak could not be precisely defined, the most likely location of the QTL is within a 4-Mb region surrounding JA04.

Peaks of linkage are localized by a BAC/PAC contig of the 6p reading disability locus.

A gene for reading disability has been localized by nonparametric linkage to 6p21.3-p22 in several published reports. However, the lack of an uninterrupted genomic clone contig has made it difficult to determine accurate intermarker distances, precise marker order, and genetic boundaries and hinders direct comparisons of linkage. The search and discovery of the hemochromatosis gene (HFE) led to the creation of a bacterial artificial chromosome (BAC) and P-1 derived artificial chromosome (PAC) contig that extended physical maps 4 Mb from the MHC toward pter and localized new markers in that region [10-12]. Using this contig, we localized 124 sequence tagged sites, expressed sequence tags, and short tandem repeats including most of the markers in linkage with reading disability phenotypes, succinic semialdehyde dehydrogenase, GPLD1, prolactin, and 18 uncharacterized genes. This new contig joins and extends previously published physical maps to span the entire chromosome 6 reading disability genetic locus. Physical mapping data from the complete contig show overlap of the published linkage peaks for reading disability, provide accurate intermarker distances and order, and offer resources for generating additional markers and candidate genes for high resolution genetic studies in this region.