Developmental dyslexia susceptibility genes DNAAF4, DCDC2, and NRSN1 are associated with brain function in fluently reading adolescents and young adults.

Reading skills and developmental dyslexia, characterized by difficulties in developing reading skills, have been associated with brain anomalies within the language network. Genetic factors contribute to developmental dyslexia risk, but the mechanisms by which these genes influence reading skills remain unclear. In this preregistered study (https://osf.io/7sehx), we explored if developmental dyslexia susceptibility genes DNAAF4, DCDC2, NRSN1, and KIAA0319 are associated with brain function in fluently reading adolescents and young adults. Functional MRI and task performance data were collected during tasks involving written and spoken sentence processing, and DNA sequence variants of developmental dyslexia susceptibility genes previously associated with brain structure anomalies were genotyped. The results revealed that variation in DNAAF4, DCDC2, and NRSN1 is associated with brain activity in key language regions: the left inferior frontal gyrus, middle temporal gyrus, and intraparietal sulcus. Furthermore, NRSN1 was associated with task performance, but KIAA0319 did not yield any significant associations. Our findings suggest that individuals with a genetic predisposition to developmental dyslexia may partly employ compensatory neural and behavioral mechanisms to maintain typical task performance. Our study highlights the relevance of these developmental dyslexia susceptibility genes in language-related brain function, even in individuals without developmental dyslexia, providing valuable insights into the genetic factors influencing language processing.

Early life stress, literacy and dyslexia: an evolutionary perspective.

Stress and learning co-evolved in parallel, with their interdependence critical to the survival of the species. Even today, the regulation of moderate levels of stress by the central autonomic network (CAN), especially during pre- and post-natal periods, facilitates biological adaptability and is an essential precursor for the cognitive requisites of learning to read. Reading is a remarkable evolutionary achievement of the human brain, mysteriously unusual, because it is not pre-wired with a genetic address to facilitate its acquisition. There is no gene for reading. The review suggests that reading co-opts a brain circuit centered in the left hemisphere ventral occipital cortex that evolved as a domain-general visual processor. Its adoption by reading depends on the CAN's coordination of the learning and emotional requirements of learning to read at the metabolic, cellular, synaptic, and network levels. By stabilizing a child's self-control and modulating the attention network's inhibitory controls over the reading circuit, the CAN plays a key role in school readiness and learning to read. In addition, the review revealed two beneficial CAN evolutionary adjustments to early-life stress "overloads" that come with incidental costs of school under-performance and dyslexia. A short-term adaptation involving methylation of the FKBP5 and NR3C1 genes is a liability for academic achievement in primary school. The adaptation leading to dyslexia induces alterations in BDNF trafficking, promoting long-term adaptive fitness by protecting against excessive glucocorticoid toxicity but risks reading difficulties by disruptive signaling from the CAN to the attention networks and the reading circuit.

Associative gene networks reveal novel candidates important for ADHD and dyslexia comorbidity.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is commonly associated with developmental dyslexia (DD), which are both prevalent and complicated pediatric neurodevelopmental disorders that have a significant influence on children's learning and development. Clinically, the comorbidity incidence of DD and ADHD is between 25 and 48%. Children with DD and ADHD may have more severe cognitive deficiencies, a poorer level of schooling, and a higher risk of social and emotional management disorders. Furthermore, patients with this comorbidity are frequently treated for a single condition in clinical settings, and the therapeutic outcome is poor. The development of effective treatment approaches against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and treatment. In this study, we developed bioinformatical methodology for the analysis of the comorbidity of these two diseases. As such, the search for candidate genes related to the comorbid conditions of ADHD and DD can help in elucidating the molecular mechanisms underlying the comorbid condition, and can also be useful for genotyping and identifying new drug targets. RESULTS: Using the ANDSystem tool, the reconstruction and analysis of gene networks associated with ADHD and dyslexia was carried out. The gene network of ADHD included 599 genes/proteins and 148,978 interactions, while that of dyslexia included 167 genes/proteins and 27,083 interactions. When the ANDSystem and GeneCards data were combined, a total of 213 genes/proteins for ADHD and dyslexia were found. An approach for ranking genes implicated in the comorbid condition of the two diseases was proposed. The approach is based on ten criteria for ranking genes by their importance, including relevance scores of association between disease and genes, standard methods of gene prioritization, as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analyzed genes. Among the top 20 genes with the highest priority DRD2, DRD4, CNTNAP2 and GRIN2B are mentioned in the literature as directly linked with the comorbidity of ADHD and dyslexia. According to the proposed approach, the genes OPRM1, CHRNA4 and SNCA had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the most relevant genes are involved in biological processes related to signal transduction, positive regulation of transcription from RNA polymerase II promoters, chemical synaptic transmission, response to drugs, ion transmembrane transport, nervous system development, cell adhesion, and neuron migration. CONCLUSIONS: The application of methods of reconstruction and analysis of gene networks is a powerful tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance for the comorbid condition of ADHD and dyslexia was employed to predict genes that play key roles in the development of the comorbid condition. The results can be utilized to plan experiments for the identification of novel candidate genes and search for novel pharmacological targets.

Dyslexia-related loci are significantly associated with language and literacy in Chinese-English bilingual Hong Kong Chinese twins.

A recent genome-wide association study on dyslexia in 51,800 affected European adults and 1,087,070 controls detected 42 genome-wide significant single nucleotide variants (SNPs). The association between rs2624839 in SEMA3F and reading fluency was replicated in a Chinese cohort. This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese-English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r2 = 0.995), and some genetic overlaps in word reading and spelling (r2 = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305-308) and the within-twin level (n = 342-344 [171-172 twin pairs]). All the three SNPs showed significant associations with quantitative Chinese and English vocabulary knowledge (p < 0.05). The strongest association after multiple testing correction was between rs12494414 and English vocabulary knowledge at the within-twin level (p = 0.004). There was a trend of associations with word reading and spelling in English but not in Chinese. Our result suggested that the region near rs2624839 is one of the common genetic factors across English and Chinese vocabulary knowledge and unique factors of English word reading and English spelling in bilingual Chinese twins. A larger sample size is required to validate our findings. Further studies on the relationship between variable expression of SEMA3F, which is important to neurodevelopment, and language and literacy are encouraged.

The Dyslexia-associated gene KIAA0319L is involved in neuronal migration in the developing chick visual system.

The gene KIAA0319-Like (KIAA0319L) is thought to confer susceptibility for developmental dyslexia. Dyslexia may be caused by alterations in neuronal migration, and in utero knockdown of KIAA0319L in rats indicated migration errors. However, studies carried out with KIAA0319L knockout mice did not reveal an altered neuronal migration phenotype. Gene knockout may activate compensatory mechanisms to buffer against genetic mutations during development. Here we assessed the role of KIAA0319L on migrating neurons in the chick developing tectum. Whole mount in situ hybridization was performed for KIAA0319L on embryonic day (E)3 - E5 chick embryos and in situ hybridization on sections was performed at later stages. The specificity and efficiency of engineered microRNA (miRNA) constructs targeting KIAA0319L for knocking down KIAA0319L were verified. miRNAs were electroporated into E5 chick optic tecta. Our studies demonstrate that KIAA0319L is expressed in the developing chick visual system, as well as in the otic vesicles. Knockdown of KIAA0319L in the optic tectum results in abnormal neuronal migration, strengthening the argument that KIAA0319L is involved in this developmental process.

[Genetic background of dyslexia and dysgraphy in children]. / Geneticheskie predposylki disleksii i disgrafii u detei.

The review is devoted to one of the current problems of pediatric neurology - reading and writing disorders in children as part of a partial developmental disorder. With the development of neuroscience, the paradigm of «brain damage¼ in the understanding of a number of pathological conditions was replaced by the concept of «evolutionary neurology¼. The dominance of the ontogenetic approach caused the appearance of a new section in ICD-11 - «Neurodevelopmental disorders¼. Twenty-one genes associated with the acquisition of reading and writing skills have been identified. Modern studies demonstrate the connection of neuropsychological prerequisites for reading and writing, and clinical phenotypes of dyslexia with changes in specific loci. It is assumed that there are different molecular genetic bases for dyslexia and dysgraphia depending on ethnicity, orthographic features of language, including logographic features. Pleiotropy of genes is a cause of comorbidity of reading and writing disorders with attention deficit and hyperactivity disorder, specific speech articulation disorders, and dyscalculia. A key function of many of the identified genes is their involvement in the processes of neurogenesis. Their dysfunctions cause atypical neuronal migration, ectopic formation, inadequate axonal growth, and dendrite branching at the early stage of brain development. Morphological changes can distort the correct distribution and/or integration of linguistic stimuli in critical brain areas, leading to abnormalities in phonology, semantics, spelling, and general reading comprehension. The knowledge gained can form the basis for the development of risk models for dysgraphia and dyslexia formation and be used as a diagnostic and/or screening tool, which is important for evidence-based correction, optimization of academic performance, and mitigation of psychosocial consequences.

Cumulative genetic score of KIAA0319 affects reading ability in Chinese children: moderation by parental education and mediation by rapid automatized naming.

KIAA0319, a well-studied candidate gene, has been shown to be associated with reading ability and developmental dyslexia. In the present study, we investigated whether KIAA0319 affects reading ability by interacting with the parental education level and whether rapid automatized naming (RAN), phonological awareness and morphological awareness mediate the relationship between KIAA0319 and reading ability. A total of 2284 Chinese children from primary school grades 3 and 6 participated in this study. Chinese character reading accuracy and word reading fluency were used as measures of reading abilities. The cumulative genetic risk score (CGS) of 13 SNPs in KIAA0319 was calculated. Results revealed interaction effect between CGS of KIAA0319 and parental education level on reading fluency. The interaction effect suggested that individuals with a low CGS of KIAA0319 were better at reading fluency in a positive environment (higher parental educational level) than individuals with a high CGS. Moreover, the interaction effect coincided with the differential susceptibility model. The results of the multiple mediator model revealed that RAN mediates the impact of the genetic cumulative effect of KIAA0319 on reading abilities. These findings provide evidence that KIAA0319 is a risk vulnerability gene that interacts with environmental factor to impact reading abilities and demonstrate the reliability of RAN as an endophenotype between genes and reading associations.

Dyslexia-Related Hearing Loss Occurs Mainly through the Abnormal Spontaneous Electrical Activity of Spiral Ganglion Neurons.

Dyslexia is a reading and spelling disorder due to neurodevelopmental abnormalities and is occasionally found to be accompanied by hearing loss, but the reason for the associated deafness remains unclear. This study finds that knockout of the dyslexia susceptibility 1 candidate 1 gene (Dyx1c1-/- ) in mice, the best gene for studying dyslexia, causes severe hearing loss, and thus it is a good model for studying the mechanism of dyslexia-related hearing loss (DRHL). This work finds that the Dyx1c1 gene is highly expressed in the mouse cochlea and that the spontaneous electrical activity of inner hair cells and type I spiral ganglion neurons is altered in the cochleae of Dyx1c1-/- mice. In addition, primary ciliary dyskinesia-related phenotypes such as situs inversus and disrupted ciliary structure are seen in Dyx1c1-/- mice. In conclusion, this study gives new insights into the mechanism of DRHL in detail and suggests that Dyx1c1 may serve as a potential target for the clinical diagnosis of DRHL.

Identification of brain cell types underlying genetic association with word reading and correlated traits.

Neuroimaging studies implicate multiple cortical regions in reading ability/disability. However, the neural cell types integral to the reading process are unknown. To contribute to this gap in knowledge, we integrated genetic results from genome-wide association studies for word reading (n = 5054) with gene expression datasets from adult/fetal human brain. Linkage disequilibrium score regression (LDSC) suggested that variants associated with word reading were enriched in genes expressed in adult excitatory neurons, specifically layer 5 and 6 FEZF2 expressing neurons and intratelencephalic (IT) neurons, which express the marker genes LINC00507, THEMIS, or RORB. Inhibitory neurons (VIP, SST, and PVALB) were also found. This finding was interesting as neurometabolite studies previously implicated excitatory-inhibitory imbalances in the etiology of reading disabilities (RD). We also tested traits that shared genetic etiology with word reading (previously determined by polygenic risk scores): attention-deficit/hyperactivity disorder (ADHD), educational attainment, and cognitive ability. For ADHD, we identified enrichment in L4 IT adult excitatory neurons. For educational attainment and cognitive ability, we confirmed previous studies identifying multiple subclasses of adult cortical excitatory and inhibitory neurons, as well as astrocytes and oligodendrocytes. For educational attainment and cognitive ability, we also identified enrichment in multiple fetal cortical excitatory and inhibitory neurons, intermediate progenitor cells, and radial glial cells. In summary, this study supports a role of excitatory and inhibitory neurons in reading and excitatory neurons in ADHD and contributes new information on fetal cell types enriched in educational attainment and cognitive ability, thereby improving our understanding of the neurobiological basis of reading/correlated traits.

Sex-related differences in reading achievement.

Over the last 40 years, ever-growing interest in sex-related differences in the human brain has led to a vast amount of literature on the subject, a small part of which relates to studies of differences in the ability to read. The data concerning typically developing children mainly come from school-based screening projects (Programme for International Student Assessment, INVALSI) and partially from the standardization of reading tests. These have revealed the existence of a gap in favor of females that primarily appears during adolescence and in situations of sociocultural disadvantage, usually explained on the basis of environmental factors such as socioeconomic status and gender-based education. Dyslexia is a neurodevelopmental disorder that is significantly more prevalent among males, a difference that neuroimaging and genetic studies have attributed to the presence of hormone-related protective factors in females, although it has been hypothesized that a different neurocognitive substrate may also be involved. However, the literature on the subject is still limited, and further studies of the interactions between genetic risk, environmental factors, and brain phenotypes are needed to clarify why females are better at performing reading tasks and less susceptible to dyslexia, regardless of their language or the educational system in the country in which they live. The aim of this mini-review was to describe the studies that have investigated sex-related differences in reading ability in both typically and atypically developing subjects.

A genome-wide association study identifies a new variant associated with word reading fluency in Chinese children.

Reading disability exhibited defects in different cognitive domains, including word reading fluency, word reading accuracy, phonological awareness, rapid automatized naming and morphological awareness. To identify the genetic basis of Chinese reading disability, we conducted a genome-wide association study (GWAS) of the cognitive traits related to Chinese reading disability in 2284 unrelated Chinese children. Among the traits analyzed in the present GWAS, we detected one genome-wide significant association (p < 5 × 10-8 ) on word reading fluency for one SNP on 4p16.2, within EVC genes (rs6446395, p = 7.33 × 10-10 ). Rs6446395 also showed significant association with Chinese character reading accuracy (p = 2.95 × 10-4 ), phonological awareness (p = 7.11 × 10-3 ) and rapid automatized naming (p = 4.71 × 10-3 ), implying multiple effects of this variant. The eQTL data showed that rs6446395 affected EVC expression in the cerebellum. Gene-based analyses identified a gene (PRDM10) to be associated with word reading fluency at the genome-wide level. Our study discovered a new candidate susceptibility variant for reading ability and provided new insights into the genetics of developmental dyslexia in Chinese children.

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion.

The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

A systematic review of associations between genetic polymorphism and dyslexia in the Indian population.

There is growing interest in understanding the genetic mechanisms underlying dyslexia. Accordingly, the literature on dyslexia is replete with shreds of evidence linking genes and their genetic markers with dyslexia among different populations. Even though genetic inquiries into dyslexia in the Asian population has gained interest in recent years, very little is known about the genes and their polymorphisms associated with dyslexia in the Indian population. To this end, we provide a systematic literature review that yields a dossier of genetic research that manifests the effect of the genes and their polymorphisms associated with dyslexia susceptibility in the Indian population. We conclude that the polymorphisms of the DYX1C1 and KIAA0319 genes deserve attention in replication studies on the Indian population in order to gain insight into the genetic etiology of dyslexia.

Discovery of 42 genome-wide significant loci associated with dyslexia.

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

Interaction between manganese and SLC6A3 genetic polymorphisms in relation to dyslexia.

BACKGROUND: Excessive exposure to manganese is harmful for neurodevelopment, causing intellectual disability, decreased cognitive ability and diminished language quotients. However, little is known about the link between manganese, genetic susceptibility and the risk of dyslexia. We aim to examine the association between manganese exposure and dyslexia and to test whether the SLC6A3 gene would modify this relationship. METHODS: A case-control study was conducted among 239 dyslexic children and 230 controls in China. Urinary manganese concentrations were assessed by inductively coupled plasma mass spectrometry (ICP-MS). Two single nucleotide polymorphisms (rs2975226 and rs27072) in the SLC6A3 gene were selected. RESULTS: The rs2975226 polymorphism was associated with dyslexia within the recessive model (OR = 1.74, 95 % CI = 1.06-2.86) and the additive model (OR = 1.69, 95 % CI = 1.10-2.61) after multivariate adjustment. Modification effects on the relationship of manganese levels in urine with the risk of dyslexia were suggested in rs27072 (P-value for interaction = 0.003). Furthermore, the highest quartile of urinary manganese was found to have a 3.87-fold (95 % CI = 1.39-10.74) elevated dyslexia risk compared with the lowest quartile among the rs27072 mutation carriers. CONCLUSIONS: The rs2975226 polymorphism was associated with dyslexia and manganese exposure could interact with the rs27072 mutation to increase the risk of dyslexia.

Case Report: Novel STIM1 Gain-of-Function Mutation in a Patient With TAM/STRMK and Immunological Involvement.

Gain-of-function (GOF) mutations in STIM1 are responsible for tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), a clinically overlapping multisystemic disease characterised by muscle weakness, miosis, thrombocytopaenia, hyposplenism, ichthyosis, dyslexia, and short stature. Several mutations have been reported as responsible for the disease. Herein, we describe a patient with TAM/STRMK due to a novel L303P STIM1 mutation, who not only presented clinical manifestations characteristic of TAM/STRMK but also manifested immunological involvement with respiratory infections since childhood, with chronic cough and chronic bronchiectasis. Despite the seemingly normal main immunological parameters, immune cells revealed GOF in calcium signalling compared with healthy donors. The calcium flux dysregulation in the immune cells could be responsible for our patient's immune involvement. The patient's mother carried the mutation but did not exhibit TAM/STRMK, manifesting an incomplete penetrance of the mutation. More cases and evidence are necessary to clarify the dual role of STIM1 in immune system dysregulation and myopathy.

Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice.

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca2+ entry due to gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1R304W/+ mice with Orai1+/- mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1R304W/+Orai1+/- mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues.

Rapid auditory processing and medial geniculate nucleus anomalies in Kiaa0319 knockout mice.

Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0319 as a main candidate. Animal models targeting the rodent homolog (Kiaa0319) have been used to explore putative behavioral and anatomic anomalies, with mixed results. For example after downregulation of Kiaa0319 expression in rats via shRNA, significant adult rapid auditory processing impairments were reported, along with cortical anomalies reflecting atypical neuronal migration. Conversely, Kiaa0319 knockout (KO) mice were reported to have typical adult auditory processing, and no visible cortical anomalies. To address these inconsistencies, we tested Kiaa0319 KO mice on auditory processing tasks similar to those used previously in rat shRNA knockdown studies. Subsequent neuroanatomic analyses on these same mice targeted medial geniculate nucleus (MGN), a receptive communication-related brain structure. Results confirm that Kiaa0319 KO mice exhibit significant auditory processing impairments specific to rapid/brief stimuli, and also show significant volumetric reductions and a shift toward fewer large and smaller neurons in the MGN. The latter finding is consistent with post mortem MGN data from human dyslexic brains. Combined evidence supports a role for KIAA0319 in the development of auditory CNS pathways subserving rapid auditory processing functions critical to the development of speech processing, language, and ultimately reading. Results affirm KIAA0319 variation as a possible risk factor for dyslexia specifically via anomalies in central acoustic processing pathways.

Infancy and early childhood maturation of neural auditory change detection and its associations to familial dyslexia risk.

OBJECTIVE: We investigated early maturation of the infant mismatch response MMR, including mismatch negativity (MMN), positive MMR (P-MMR), and late discriminative negativity (LDN), indexing auditory discrimination abilities, and the influence of familial developmental dyslexia risk. METHODS: We recorded MMRs to vowel, duration, and frequency deviants in pseudo-words at 0, 6, and 28 months and compared MMRs in subgroups with vs. without dyslexia risk, in a sample over-represented by risk infants. RESULTS: Neonatal MMN to the duration deviant became larger and earlier by 28 months; MMN was elicited by more deviants only at 28 months. The P-MMR was predominant in infancy; its amplitude increased by 6 and decreased by 28 months; latency decreased with increasing age. An LDN emerged by 6 months and became larger and later by 28 months. Dyslexia risk affected MMRs and their maturation. CONCLUSIONS: MMRs demonstrate an expected maturational pattern with 2-3 peaks by 28 months. The effects of dyslexia risk are prominent but not always as expected. SIGNIFICANCE: This large-scale longitudinal study shows MMR maturation with three age groups and three deviants. Results illuminate MMR's relation to the adult responses, and hence their cognitive underpinnings, and help in identifying typical/atypical auditory development in early childhood.