Dr Dianne Newbury

Recent work putatively linked a rare genetic variant of the chaperone Resistant to Inhibitors of acetylcholinesterase (RIC3) (NM_024557.4:c.262G>A, NP_078833.3:p.G88R) to a unique ability to speak backwards, a language skill that is associated with exceptional working memory capacity. RIC3 is important for the folding, maturation and functional expression of α7 nicotinic acetylcholine receptors (nAChR). We compared and contrasted the effects of RIC3G88R on assembly, cell surface expression and function of human α7 receptors using fluorescent protein tagged α7 nAChR and Förster resonance energy transfer (FRET) microscopy imaging in combination with functional assays and 125I-α-bungarotoxin binding. As expected, the wildtype RIC3 protein was found to increase both cell surface and functional expression of α7 receptors. In contrast, the variant form of RIC3 decreased both. FRET analysis showed that RICG88R increased the interactions between RIC3 and α7 protein in the Endoplasmic Reticulum. These results provide interesting and novel data to show that a RIC3 variant alters the interaction of RIC3 and α7, which translates to decreased cell surface and functional expression of α7 nAChR.

Purpose: Young people with developmental language disorder (DLD) have poorer mental health than those without DLD. However, not all young people with DLD are equally affected; some have more mental health difficulties than others. What explains these differences remains unclear.

Method: Data from a community cohort study, the Avon Longitudinal Study of Parents and Children, was analysed to investigate genetic and environmental influences on the development of mental health difficulties at five time points from childhood (7 years) to adolescence (16 years) in 6,387 young people (8.7% with DLD). Regression and latent class models were fitted to the data.

Results: Polygenic scores, indices of genetic risk, for common psychiatric disorders (major depressive disorder, anxiety disorder, and attention deficit hyperactivity disorder) predicted mental health difficulties in both groups (with and without DLD). The presence of DLD, in some instances, amplified mental health difficulties for those with high genetic risk for common psychiatric disorders. Sub-groups of children with similar developmental trajectories of mental health difficulties were identified. Young people with DLD were more likely than those without DLD to follow mental health sub-groups characterised by consistently high levels of difficulties during development. Polygenic scores, socioeconomic status, and the early home environment distinguished sub-groups with low mental health difficulties from those characterised by high levels of difficulties, but these effects did not differ based on DLD status.

Conclusion. These findings suggest that, for the most part, both genetic and environmental risk affect the development of mental health difficulties in a cumulative way for young people with DLD (and those without). Some analysis did, however, suggest that genetic risk for common psychiatric disorders might manifest more strongly in those with DLD compared to those without DLD.

Orofacial cleft (OC) is a common congenital anomaly in humans which has lifelong implications for affected individuals. This disorder can be classified as syndromic or non-syndromic depending on the presence or absence of additional physical or neurodevelopmental abnormalities respectively. Non-syndromic cleft is often non-familial in nature and has a complex aetiology while syndromic forms tend to be monogenic. Although individual OC-related syndromes have been frequently described in the medical literature, there has not been a comprehensive review across syndromes, thereby leaving a gap in our knowledge, which this paper aims to address. Six hundred and three patients with cleft-related HPO terms were identified within the Deciphering Developmental Disorders (DDD) study. Genes carrying pathogenic/likely pathogenic variants were identified and reviewed enabling a diagnostic yield of 36.5%. In total, 124 candidate genes for syndromic OC were identified, including 34 new genes that should be considered for inclusion in clinical clefting panels. Functional enrichment and gene expression analyses identified 3 key processes that were significantly over-represented in syndromic OC gene lists: embryonic morphogenesis, protein stability and chromatin organisation. Comparison with non-syndromic OC gene networks led us to propose that chromatin remodelling specifically contributes to the aetiology of syndromic OC. Disease-driven gene discovery is a valid approach to gene identification and curation of gene panels. Through this approach we have started to unravel common molecular pathways contributing to syndromic orofacial clefting.

Handedness has been studied for association with language-related disorders because of its
link with language hemispheric dominance. No clear pattern has emerged, possibly because
of small samples, publication bias, and heterogeneous criteria across studies.

We assessed the frequency of non-right handedness (NRH) in N = 2,503 cases with reading
and/or language impairment and N = 4,316 sex-matched controls identified from 10 distinct
cohorts (age range 6-19 years old) using a priori set criteria. A meta-analysis (N cases = 1,994)
showed elevated NRH % in individuals with language/reading impairment compared to
controls (OR = 1.21, CI = 1.06 - 1.39, p = 0.01).

The association between reading/language impairments and NRH could result from shared
pathways underlying brain lateralization, handedness, and cognitive functions.

Reading and writing are crucial life skills but roughly 1 in 10 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. Our genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls identified 42 independent significant loci: 15 in genes linked to cognitive ability/educational attainment; 27 novel and potentially more specific to dyslexia. Twenty-three loci (13 novel) were validated in independent cohorts of Chinese and European ancestry. Genetic aetiology 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.

Objective: To report how improvements on a Brazilian language intervention for early childhood education settings (PROLIN) were made and evaluated.

Study Design: In the first phase, the programme layout and materials were improved. This involved redesigning the guidelines for the programme, adding videos (using a learning management system) and creating an observation checklist to monitor the fidelity of implementation. The second phase was a two-week pilot study (a 7-session intervention) involving two teachers and 22 students. Checklists and video footage were analysed to investigate implementation.

Results: Quality of implementation was generally good, but we identified additional areas for improvement. Teachers had some difficulties with aspects related to session dynamics, implementation of activities and use of techniques that reinforce learning.

Conclusions:  The pilot study was instrumental in identifying obstacles for a scaled-up, high-quality implementation. The design of these materials took into consideration ways of guiding and supporting teachers:(1) to offer students adequate participation time; (2) to help include children who are shy or have behaviour problems; (3) to use teaching strategies properly; (4) to bring sessions to a close; and (5) to reach the objectives of each session. Further modification is still needed, especially in the manual, videos and supplementary materials.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, in samples of 13,633 to 33,959 participants aged 5-26 years. We identified genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP-heritability, accounting for 13-26% of trait variability. Genomic structural equation modelling revealed a shared genetic factor explaining most variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain, and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of uniquely human traits.

The negative health effects cigarette smoking during pregnancy (SDP) on the foetus are well known. Despite previous reports of poor cognitive performance in offspring exposed to SDP, few studies specifically consider language outcomes according to maternal smoking. In this study, we systematically review the literature to assess the relationships between SDP and child language. Of the 14 studies reviewed, 13 (93%) reported significant associations between maternal smoking or exposure and language outcomes. Despite this consistent association, only 8 of the 13 studies reporting associations (62%) concluded direct relationships between exposure and outcome. The remaining studies suggested that the relationship between smoking and language could be explained by factors such as maternal IQ, socioeconomic status (SES) and parental age. Future studies should apply careful study designs allowing for confounding factors across child, parental, environmental and genetic influences. Our review suggests that smoking cessation is likely to positively affect child language outcomes.

Research in the UK suggests that multi-componential interventions focusing on language and pre-literacy skills can improve children’s reading and language skills. However, simple translations of such programs may not produce equivalent effects in diverse communities. The reasons for this are multi-faceted and include factors beyond the rationale and content of the intervention programs themselves. Understanding these factors is critical for creating programs that will generalise across settings. In this review, we reflect upon challenges encountered in two reading and language intervention programs in South America to identify community and cultural contextual factors that can influence the implementation and scalability of educational programs. We use our findings to develop an education-specific framework to guide the development and implementation of high-quality evidence-based approaches to language and literacy intervention. Our model guides implementation practices in diverse contexts and stresses the importance of the evidence-base and communication.

Language disorders are highly heritable and are influenced by complex interactions between genetic and environmental factors. Despite more than twenty years of research, we still lack critical understanding of the biological underpinnings of language. This review provides an overview of the genetic landscape of developmental language disorders (DLD), with an emphasis on the importance of defining the specific features (the phenotype) of DLD to inform gene discovery. We review the specific phenotype of DLD in the genetic literature, and the influence of historic variation in diagnostic inclusion criteria on researchers’ ability to compare and replicate genotype-phenotype studies. This review provides an overview of the recently identified gene pathways in populations with DLD and explores current state-of-the-art approaches to genetic analysis based on the hypothesized architecture of DLD. We will show how recent global efforts to unify diagnostic criteria have vastly increased sample size and allow for large multi-cohort metanalyses, leading the identification of a growing number of contributory loci. We emphasize the important role of estimating the genetic architecture of DLD to decipher underlying genetic associations. Finally, we explore the potential for epigenetics and environmental interactions to further unravel the biological basis of language disorders.  

BACKGROUND: Recent studies have highlighted a role for trace trace elements and toxic metals across neurodevelopmental disorders including developmental stuttering, Autistic Spectrum Disorders (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD). However, these environmental influences have yet to be explored in relation to Developmental Language Disorder (DLD).

METHODS: Elemental hair composition of 7 elements; zinc (64Zn), magnesium (26Mg), iron (57Fe), potassium (39K), aluminum (27Al), lead (208Pb), and barium (138Ba) were analyzed in hair samples from 35 children affected by DLD and 35 controls with typical language development (TLD) using both inductive coupled plasma optical emission spectroscopy (ICP–OES) and inductive coupled plasma mass spectroscopy (ICP–MS).

RESULTS: The concentration of 64Zn was significantly lower in the hair of DLD group compared to the TLD control group. All other elements showed similar levels between cases and controls. This pilot study demonstrates the utility of trace elements and toxic metals screening in relation to language disorders and the use of hair samples in such investigations.

CONCLUSION: The finding that zinc levels differed between cases and controls could represent a clinically relevant result and should be replicated in a larger sample size across time. A wider battery of related elements will help to better understand the role of trace elements and toxic metals in DLD.

The ability to finely control our movement is key to the achieving many of the educational milestones and life-skills we develop throughout our lives. Despite the centrality of coordination to our early development, there is a vast gap in our understanding of the underlying biology. Like most complex traits, both genetics and environment influence motor coordination, however, the specific genes, early environmental risk factors and molecular pathways are unknown.

Previous studies have shown that about 5% of school-age children experience unexplained difficulties with motor coordination. These children are said to have Developmental Coordination Disorder (DCD). For children with DCD, these motor coordination difficulties significantly impact their everyday life and learning. DCD is associated with poorer academic achievement, reduced quality of life, it can constrain career opportunities and increase the risk of mental health issues in adulthood. Despite the high prevalence of coordination difficulties, many children remain undiagnosed by healthcare professionals. Compounding under-diagnosis in the clinic, research into the etiology of DCD is severely underrepresented in the literature.

Here we present the first genome-wide association study (GWAS) to examine the genetic basis of early motor coordination in the context of motor difficulties. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we generate a derived measure of motor coordination from four components of the Movement Assessment Battery for Children (MABC), providing an overall measure of coordination across the full range of ability. We perform the first genome-wide association analysis focused on motor coordination (N=4542). No single nucleotide polymorphisms (SNPs) met the threshold for genome-wide significance however 59 SNPs showed suggestive associations. Three regions contained multiple suggestively associated SNP, within five preliminary candidate genes: IQSEC1, LRCC1, SYNJ2B2, ADAM20 and ADAM21.

Association to the gene IQSEC1 suggests a potential link to axon guidance and dendritic projection processes as a potential underlying mechanism of motor coordination difficulties. This represents an interesting potential mechanism, and whilst further validation is essential, it generates a direct window into the biology of motor coordination difficulties. This research has identified potential biological drivers of DCD, a first step towards understanding this common, yet neglected neurodevelopmental disorder.

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N=360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24,046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N=42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N=1825; minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, USH2A. In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous USH2A mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is “phenotype free”. Parallel evidence has confirmed that heterozygous Ush2a mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and not central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous Ush2a mice. We found that heterozygous Ush2a mice had significantly larger SOC volumes while homozygous Ush2a had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous Ush2a mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to USH2A variation can secondarily impact the development of brain regions important for auditory processing ability.

Background: Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing.
Methods: We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9.
Results: Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects.
Conclusions: We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.

The quality of a child’s early language and communication environment (ELCE) is an important predictor of later educational outcomes. However, less is known about the routes via which these early experiences influence the skills that support academic achievement.  Using data from the Avon Longitudinal Study of Parents and Children (n=7,120) we investigated relations between ELCE (

ELCE was a significant, direct predictor of social adjustment and literacy skills at school entry and of linguistic and social competence at 7-9 years. ELCE did not directly explain variance in literacy outcomes at the end of primary school, instead the influence was exerted via indirect paths through literacy and social adjustment aged 5, and, language development and social development at 7-9 years. Linguistic and social skills were both predictors of literacy skills at the end of primary school. 
Findings are discussed with reference to their potential implications for the timing and targets of interventions designed to improve literacy outcomes. 

Studies examining genetic conditions common in Latin America are highly underrepresented in the scientific literature. Understanding of the population structure is limited, particularly Chile, in part due to the lack of available population specific data. An important first-step in elucidating disease mechanisms in Latin America countries is to understand the genetic structure of isolated populations. Robinson Crusoe Island (RCI) is a small land mass off the coast of Chile. The current population of over 900 inhabitants are primarily descended from a small number of founders who colonized the island in the late 1800s. Extensive genealogical records can trace the ancestry of almost the entire population. We perform a comprehensive genetic analysis to investigate the ancestry of the island population, examining ancestral mitochondrial and Y chromosome haplogroups, as well as autosomal admixture. Mitochondrial and Y chromosome haplogroups indicated a substantial European genetic contribution to the current RCI population. Analysis of the mitochondrial haplogroups found in the present-day population revealed that 79.1% of islanders carried European haplogroups, compared to 60.0% of the mainland Chilean controls from Santiago. Both groups showed a substantially lower contribution of indigenous haplogroups than expected. Analysis of the Y chromosome haplogroups also showed predominantly European haplogroups detected in 92.3% of male islanders and 86.7% of mainland Chilean controls. Using the near-complete genealogical data collected from the RCI population, we successfully inferred the ancestral haplogroups of 16/23 founder individuals, revealing genetic ancestry from Northern and Southern Europe. As mitochondrial and Y investigations only provide information for direct maternal and paternal lineages, we expanded this to investigate genetic admixture using the autosomes. Admixture analysis identified substantial indigenous genetic admixture in the RCI population (46.9%), higher than that found in the Santiago mainland Chilean controls (43.4%), but lower than a more representative Chilean population (Chile_GRU) (49.1%). Our study revealed the Robinson Crusoe Island population show a substantial genetic contribution for indigenous Chileans, similar to the level reported in mainland Chileans. However, direct maternal and paternal haplogroup analysis revealed strong European genetic contributions consistent with the history of the Island.

Background: Children with developmental language disorder (DLD) are at higher risk of poorer mental health compared to children without DLD. There are, however, considerable individual differences that need to be interpreted, including the identification of protective factors.  
Aims:  Pathways from the early language and communication environment (ELCE, 1-2 years) to internalising (peer and emotional problems) and externalising (conduct problems and hyperactivity) problems in middle childhood (11 years) were mapped using structural equation modelling.  Specifically, the role of indirect pathways via social skills (friendships, play, and prosociality) in childhood (7-9 years) was investigated.
Methods and Procedures: Secondary analysis of existing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) was undertaken.  The study sample consisted of 6,531 children (394 with DLD).  
Outcomes and Results: The pathways from the ELCE to internalising and externalising problems were similar for children with and without DLD.  For both groups, a positive ELCE was associated with more competent social play and higher levels of prosociality in childhood, which in turn were associated with fewer externalising problems in middle childhood.  Furthermore, better friendships and higher levels of prosociality in childhood were both associated with fewer internalising problems in middle childhood.    
Conclusions and Implications: A child’s ELCE is potentially important not only for the development of language but also for social development.  Furthermore, in the absence of adequate language ability, play and prosocial behaviours may allow children with DLD to deploy, practise, and learn key social skills, thus protecting against externalising problems.    We suggest that consideration be given to play- and prosociality-based educational and therapeutic services for children with DLD.

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)—stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss‐of‐function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within‐group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.

This study explored the effects of a 27-week reading and language intervention, for low-income children living in a remote Chilean community, using a randomized controlled trial. At the end of the intervention, children in the intervention group showed improvements compared to the waiting group on pre-literacy, reading, language, and reading comprehension measures (effect sizes d >.25). The gains in pre-literacy skills, word reading and word knowledge were maintained at 9-month delayed follow-up, though the improvements in language and reading comprehension were not. Intervention programs designed to support literacy and language skills in remote communities can be delivered successfully by trained assistants. Our findings suggest that language and literacy programs can be useful for improving attainment in children living in disadvantaged and isolated communities.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems. 

Purpose: Children with poor language tend to have worse psychosocial outcomes compared to their typically developing peers.  The most common explanations for such adversities focus on developmental psychological processes whereby poor language triggers psychosocial difficulties.  Here we investigate the possibility of shared biological effects by considering whether the same genetic variants which are thought to influence language development are also predictors of elevated psychosocial difficulties during childhood.  

Method: Using data from the UK based Avon Longitudinal Study of Parents and Children (ALSPAC) we created a number of multi-SNP polygenic profile scores, based on language and reading candidate genes (ATP2C2, CMIP, CNTNAP2, DCDC2, FOXP2, & KIAA0319, 1229 SNPs) in a sample of 5,435 children. 

Results: A polygenic profile score for expressive language (8 years) that was created in a discovery sample (n=2,718), predicted not only expressive language (8 years), but also peer problems (11 years) in a replication sample (n=2,717).  

Conclusions: These findings provide a proof of concept for the use of such a polygenic approach in child language research when larger datasets become available.  Our indicative findings suggest consideration should be given to concurrent intervention targeting both linguistic and psychosocial development as early language interventions may not stave off later psychosocial difficulties in children.

Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. 

Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. We go on to test whether the overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. 

In the absence of explanatory rare variants, we further investigate these candidate genes within a complex model of inheritance, where inheriting a small number of moderate impact common variants may increase susceptibility of developing TEL. We examine if any variants segregate with affection status or with founder-brother-related status, and therefore may increase risk of developing a language disorder. Finally, we perform a pooled, gene-based tests to evaluate relationships between combined variation across candidate genes and TEL affection status.

Here we report a comprehensive examination of genes directly implicated in language-related mechanisms to identify ‘low hanging fruit’ of causative monogenic Mendelian variants, and complex association model of increased susceptibility in developmental language disorder found on Robinson Crusoe Island.

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions.

Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis.

Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association.

Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome.

Background

We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex chromosomal rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.

Results

Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells.

Conclusions

We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.

Aim

Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia.

Method

Genome‐wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years).

Results

In the clinical language‐impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified.

Interpretation

The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non‐verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals.

Background: Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals

affected by language impairment. Methods: We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types. Results: Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types  indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD). Conclusion: These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.

The forkhead box P2 gene, designated FOXP2, is the first gene implicated in

a speech and language disorder. Since its discovery, many studies have been

carried out in an attempt to explain the mechanism by which it influences these

characteristically human traits. This review presents the story of the discovery

of the FOXP2 gene, including early studies of the phenotypic implications of a

disruption in the gene. We then discuss recent investigations into the molecular

function of the FOXP2 gene, including functional and gene expression studies. We

conclude this review by presenting the fascinating results of recent studies of the

FOXP2 ortholog in other species that are capable of vocal communication