Academic Staff

Modules taught

P10112: Molecular Basis of Human Genetic Disease

P10114: Clinical Genetics and Diagnostics

P10199: MSc research project

U14520: Molecular Biology and Genetics

U14592: Molecular Medicine

U14675: Experimental Based Medicine and Diagnostics

U14699: Undergraduate research projects

Supervision

Research in my lab centres around genetic contributions to speech, language and Communication Disorders (SLCDs). A recent study found that, at school entry in the UK, approximately 10% of children are affected by speech, language or communication impairments (Norbury et al., 2016). As a group these children are less likely to meet educational targets (Norbury et al., 2015) and more likely to display symptoms of social, emotional and behavioural problems when compared to their peers (Norbury et al., 2016).

But yet, we do not know why some children have language difficulties or how these difficulties relate to other aspects of neurodevelopment and behaviour. In our lab, we are trying to identify genetic factors that might play a role in these disorders. We investigate this problem through a mixture of research questions and by studying individuals, families and populations.

This research is important because it will help us to understand why some children have language difficulties and what brain processes are important in language learning. It may allow us to identify new kinds of language disorders and will clarify the relationships between language impairment and other developmental disorders.

Research group membership

Hayley Mountford (post-doc) p0083144

Lidiya Nevedska (PhD student) 16034238

Nuala Simpson (post-doc) p0084691

Research grants and awards

Research Excellence (CRF) award – Functional characterisation of RIC3 in backwards speech. Aug 2016-Jan 2017

ESRC Newton Award - A language and reading intervention programme for Chile, piloted in the Robinson Crusoe population. Feb 2016 – Oct 2018

Research projects

Studies show that developmental language disorders run in families - a brother or sister of someone who has already been diagnosed will have an increased risk of developing the disorder themselves. There are two possible situations which may explain this observation: (1) something in the family environment causes the language disorder; or (2) Developmental language disorders are genetic and is therefore caused (at least in part) by the genes passed on from parents to children.

Although there is strong evidence for the role of a genetic component in language disorder, we do not know which genes contribute to this disorder or how the inheritance of language problems work. In most cases, it is likely that several genes combine to bring about a heightened risk of disorder. This is known as a complex genetic disorder. Working closely with other collaborators active in this field, we aim to identify specific genetic variants that cause this predisposition and to investigate the kinds of biological processes that they take part in.

The work in our lab is split into different project areas. You can find out more about each area on our research website.

Research impact

Journal articles

• den Hoed, J., de Boer, E., Voisin, N., Dingemans, A. J. M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S. M., Banka, S., Bena, F. S., Ben-Zeev, B., Bonagura, V. R., Bruel, A.-L., Brunet, T., Brunner, H. G., Chew, H. B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E. C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D. A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y. H., Hanebeck, J., Hehir-Kwa, J. Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K. L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A. A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M. A., Miyatake, S., Mizuguchi, T., Moey, L. H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T. B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J. A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L. S., Spillmann, R. C., Stegmann, A. P. A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J. H., Vergano, S. A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D. F., Kleefstra, T., Reymond, A., Fisher, S. E. & Vissers, L. E. L. M. , 'Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction'
  American Journal of Human Genetics x (2021)
  ISSN: 0002-9297 eISSN: 1537-6605
  Abstract

  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.
  

  Website 
• Perrino P, Newbury DF, Fitch RH, 'Peripheral anomalies in USH2A cause Central Auditory Anomalies in a Mouse Model of Usher syndrome and CAPD'
  Genes 12 (2) (2021)
  ISSN: 2073-4425
  Abstract

  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.
  

  Website 
• Thompson PA, Bishop, DVM, Eising E, Fisher SE, Newbury DF, 'Generalized Structured Component Analysis in candidate gene association studies: applications and limitations'
  Wellcome Open Research 4 (2021)
  ISSN: 2398-502X eISSN: 2398-502X
  Abstract

  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.
  

  Website 
• Gibson JL, Newbury DF, Durkin K, Pickles A, Conti-Ramsden G, Toseeb U, 'Pathways from the Early Language and Communication Environment to Literacy Outcomes at the End of Primary School; The Roles of Language Development and Social Development'
  Oxford Review of Education x (2020)
  ISSN: 0305-4985 eISSN: 1465-3915
  Abstract

  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 (<2 years), literacy and social adjustment at school entry (5 years), structural language development and social development in mid-primary school (7-9 years), and, literacy outcomes (reading and writing) at the end of primary school (11 years) using structural equation modelling.
  

  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. 
  

  Website 
• Mountford HS, Villanueva P, Fernández MA, Jara L, De Barbieri Z, Carvajal-Carmona LG, Cazier JB, Newbury DF, 'The Genetic Population Structure of Robinson Crusoe Island, Chile'
  Frontiers in Genetics 11 (2020)
  ISSN: 1664-8021 eISSN: 1664-8021
  Abstract

  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.
  

  Website 
• Toseeb U, Gibson JL, Newbury DF, Orlik W, Durkin K, Pickles A, Conti-Ramsden G, 'Play and Prosociality are Associated with Fewer Externalising Problems in Children with Developmental Language Disorder: The Role of Early Language and Communication Environment'
  International Journal of Language and Communication Disorders 55 (4) (2020) pp.583-602
  ISSN: 1368-2822 eISSN: 1460-6984
  Abstract

  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.

  Website 
• Mountford H, Bishop DVM, Thompson PA, Simpson NH, Newbury DF, 'Copy Number Variation (CNV) burden does not predict severity of Neurodevelopmental Phenotype in Children with a Sex Chromosome Trisomy'
  American Journal of Medical Genetics Part C: Seminars in Medical Genetics x (2020)
  ISSN: 1552-4868
  Abstract

  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.
  

  Website 
• Mesa C, Newbury DF, Nash M, Clarke P, Esposito R, Elliott L, De Barbieri Z, Fernandez MA, Villanueva P, Hulme C, Snowling MJ, 'The Effects of Reading and Language Intervention on Literacy Skills in Children in a Remote Community: An Exploratory Randomized Controlled Trial'
  International Journal of Educational Research 100 (2020)
  ISSN: 0883-0355
  Abstract

  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.

  Website 
• Perrino PA, Nedevska L, Reader R, Hill A, Rendall AR, Mountford HS, Taylor J, Buscarello AN, Lahiri N, Saggar A, Fitch RH, Newbury DF, 'Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes'
  Communications Biology 3 (2020)
  ISSN: 2399-3642
  Abstract

  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. 
  

  Website 
• Newbury DF, Gibson JL, Conti-Ramsden G, Pickles A, Durkin K, Toseeb U, 'Using Polygenic Profiles to Predict Variation in Language and Psychosocial Outcomes in Early and Middle Childhood'
  Journal of Speech, Language, and Hearing Research 62 (9) (2019) pp.3381-3396
  ISSN: 1092-4388 eISSN: 1558-9102
  Abstract

  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.

  Website 
• Mountford HS, Villanueva, Fernández MA, De Barbieri Z, Cazier J-B, Newbury DF, 'Candidate Gene Variant Effects on Language Disorders in Robinson Crusoe Island'
  Annals of Human Biology 46 (2) (2019) pp.109-119
  ISSN: 0301-4460 eISSN: 1464-5033
  Abstract

  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.

  Website 
• Newbury DF, Simpson NH, Thompson PA, Bishop DVM, 'Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis'
  Wellcome Open Research 3 (85) (2018)
  ISSN: 2398-502X
  Abstract

  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.

  Website 
• De Barbieri Z, Fernandez MA, Newbury DF, Villanueva P, 'Family aggregation of Language Impairment in an Isolated Chilean Population from the Robinson Crusoe Island'
  International Journal of Language and Communication Disorders 53 (3) (2018) pp.643-655
  ISSN: 1368-2822 eISSN: 1460-6984
  Abstract Background: It has been reported that the inhabitants of the Chilean Robinson Crusoe Island have an increased frequency of Specific Language Impairment (SLI) or Developmental Language Disorder (DLD). Aims: In this paper, we aim to explore the familial aggregation of DLD in this community. Methods & procedures: We assessed the frequency of DLD amongst colonial children between the ages of 3 years and 8 years, 11 months (50 individuals from 45 nuclear families). Familial aggregation rates of language-disorder were calculated by assessing all available first-degree relatives (n= 107, 77 parents, 25 siblings, 5 half-siblings) of the probands. Outcomes & results: We found that 71% of the child population performed significantly below expected in measures of phonological production or expressive and receptive morphology. The majority of these children presented with severe expressive and/or receptive language difficulties. A quarter of language disordered probands primarily had phonological difficulties. Family members of affected probands, experienced a higher risk of language-disorder than those of typically-developing probands. This increased risk was apparent regardless of nonverbal IQ. Conclusions & implications: Our study substantiates the existence of a familial form of speech and language disorder on the Robinson Crusoe Island. Furthermore, we find that the familiality is stable regardless of non-verbal IQ, supporting the recent movement to reduce the importance of nonverbal IQ criterion in DLD diagnoses.Website 
• Newbury DF, Simpson NH, Thompson PA, Bishop DVM, 'Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis'
  Wellcome Open Research 3 (10) (2018)
  ISSN: 2398-502X
  Abstract Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: 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. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed. Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (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. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.Website 
• Mountford HS, Newbury DF, 'The Genomic Landscape of Language Disorders: Insights into Evolution'
  Journal of Language Evolution 3 (1) (2018) pp.49-58
  ISSN: 2058-4571 eISSN: 2058-458X
  Abstract Studies of severe, monogenic forms of language disorders have revealed important insights into the mechanisms that underpin language development and evolution. It is clear that monogenic mutations in genes such as FOXP2 and CNTNAP2 only account for a small proportion of language disorders seen in children, and the genetic basis of language in modern humans is highly complex and poorly understood. In this review, we examine why we understand so little of the genetic landscape of language disorders, and how the genetic background of an individual greatly affects the way in which a genetic change is expressed. We discuss how the underlying genetics of language disorders has informed our understanding of language evolution, and how recent advances may obtain a clearer picture of language capacity in ancient hominins. Website 
• Grabitz CR, Button KS, Munafò MR, Newbury DF, Pernet CR, Thompson PA,Bishop DVM, 'Logical and methodological issues affecting genetic studies of humans reported in top neuroscience journals'
  Journal of Cognitive Neuroscience 30 (1) (2017) pp.25-41
  ISSN: 0898-929X eISSN: 1530-8898
  Abstract Genetics and neuroscience are two areas of science that pose particular methodological problems because they involve detecting weak signals (i.e., small effects) in noisy data. In recent years, increasing numbers of studies have attempted to bridge these disciplines by looking for genetic factors associated with individual differences in behaviour, cognition and brain structure or function. However, different methodological approaches to guarding against false positives have evolved in the two disciplines. To explore methodological issues affecting neurogenetic studies, we conducted an in-depth analysis of 30 consecutive articles in 12 top neuroscience journals that reported on genetic associations in non-clinical human samples. It was often difficult to estimate effect sizes in neuroimaging paradigms. Where effect sizes could be calculated, the studies reporting the largest effect sizes tended to have two features: (i) they had the smallest samples, and were generally underpowered to detect genetic effects; and (ii) they did not fully correct for multiple comparisons. Furthermore, only a minority of studies used statistical methods for multiple comparisons that took into account correlations between phenotypes or genotypes, and only nine studies included a replication sample, or explicitly set out to replicate a prior finding. Finally, presentation of methodological information was not standardized and was often distributed across Methods sections and Supplementary Material, making it challenging to assemble basic information from many studies. Space limits imposed by journals could mean that highly complex statistical methods were described in only a superficial fashion.  In sum, methods which have become standard in the genetics literature – stringent statistical standards, use of large samples and replication of findings – are not always adopted when behavioural, cognitive or neuroimaging phenotypes are used, leading to an increased risk of false positive findings. Studies need to correct not just for the number of phenotypes collected, but also for number of genotypes examined, genetic models tested and subsamples investigated. The field would benefit from more widespread use of methods that take into account correlations between the factors corrected for, such as spectral decomposition, or permutation approaches. Replication should become standard practice; this, together with the need for larger sample sizes, will entail greater emphasis on collaboration between research groups. We conclude with some specific suggestions for standardized reporting in this area.Website 
• Chen XS, Reader RH, Hoischen A, Veltman JA, Simpson NH, Francks C, Newbury DF, Fisher SE, 'Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment'
  Scientific Reports 7 (2017)
  ISSN: 2045-2322
  Abstract A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including 36 microtubule transport and cytoskeletal regulation.Website 
• Devanna P, Chen S, Ho J, Gajewski D, Smith SD, Gialluisi A, Francks C, Fisher SE, Newbury DF, Vernes SC, 'Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders'
  Molecular Psychiatry 23 (2017) pp.1375-1384
  ISSN: 1359-4184 eISSN: 1476-5578
  Abstract Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome are likely to play an important role in these phenotypes. Herein we show the importance of 3’UTR non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from NGS data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant, and the affected gene (ARHGEF39), represent new putative risk factors for SLI. Furthermore, we identified 3’UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.Website 
• Pettigrew KA, Frinton E, Nudel R, Chan MTM, Thompson P, Hayiou-Thomas ME, Talcott JB, Stein J, Monaco AP, Hulme C, Snowling MJ, Newbury DF, Paracchini S, 'Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes'
  Journal of Neurodevelopmental Disorders 8 (24) (2016) pp.1-8
  ISSN: 1866-1947 eISSN: 1866-1955
  Abstract Background: Specific Language Impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10% of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods: We used two independent family-based cohorts characterised with reading- and language-related traits:  a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. Results: We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions: A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits. Website 
• Shore R, Covill L, Pettigrew KA, Brandler WM, Diaz R, Xu Y, Tello JA, Talcott JB, Newbury DF, Stein J, Monaco AP, Paracchini S., 'The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts'
  Human Molecular Genetics 25 (9) (2016) pp.1771-1779
  ISSN: 0964-6906 eISSN: 1460-2083
  Abstract We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10−8) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left–right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.Website 
• Prekovic S, Đurđević DF, Csifcsák G, Šveljo O, Stojković O, Janković M, Koprivšek K, Covill LE, Lučić M, Van den Broeck T, Helsen C, Ceroni F, Claessens F, Newbury DF, 'Multidisciplinary investigation links backward-speech trait and working memory through genetic mutation.'
  Scientific Reports 6 (2016) pp.1-15
  ISSN: 2045-2322
  Abstract Case studies of unusual traits can provide unique snapshots of the effects of modified systems. In this study, we report on an individual from a Serbian family with the ability to rapidly, accurately and voluntarily speak backwards. We consider psychological, neural and genetic correlates of this trait to identify specific relevant neural mechanisms and new molecular pathways for working memory and speech-related tasks. EEG data suggest that the effect of word reversal precedes semantic integration of visually presented backward-words, and that event-related potentials above the frontal lobe are affected by both word reversal and the maintenance of backward-words in working memory. fMRI revealed that the left fusiform gyrus may facilitate the production of backward-speech. Exome sequencing identified three novel coding variants of potential significance in the RIC3, RIPK1 and ZBED5 genes. Taken together, our data suggest that, in this individual, the ability to speak backwards is afforded by an extraordinary working memory capacity. We hypothesise that this is served by cholinergic projections from the basal forebrain to the frontal cortex and supported by visual semantic loops within the left fusiform gyrus and that these neural processes may be mediated by a genetic mutation in RIC3; a chaperone for nicotinic acetylcholine receptors.Website 
• Reader RH, Covill LE, Nudel R, Newbury DF., 'Genome-Wide Studies of Specific Language Impairment'
  Current Behavioral Neuroscience Reports 1 (4) (2015) pp.242-250
  ISSN: 2196-2979
  Abstract Specific language impairment (SLI) is a multifactorial neurodevelopmental disorder which occurs unexpectedly and without an obvious cause. Over a decade of research suggests that SLI is highly heritable. Several genes and loci have already been implicated in SLI through linkage and targeted association methods. Recently, genome-wide association studies (GWAS) of SLI and language traits in the general population have been reported and, consequently, new candidate genes have been identified. This review aims to summarise the literature concerning genome-wide studies of SLI. In addition, this review highlights the methodologies that have been used to research the genetics of SLI to date, and also considers the current, and future, contributions that GWAS can offer.Website 
• Ceroni F, Simpson NH, Francks C, Baird G, Conti-Ramsden G, Clark A, Bolton PF, Hennessy ER, Donnelly P, Bentley DR, Martin H; IMGSAC; SLI Consortium; WGS500 Consortium, Parr J, Pagnamenta AT, Maestrini E, Bacchelli E, Fisher SE, Newbury DF., 'Reply to Pembrey et al: 'ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis'.'
  European Journal of Human Genetics 23 (2015) pp.1113-1115
  ISSN: 1018-4813 eISSN: 1476-5438
  Website 
• Pettigrew KA, Reeves E, Leavett R, Hayiou-Thomas ME, Sharma A, Simpson NH, Martinelli A, Thompson P, Hulme C, Snowling MJ, Newbury DF, Paracchini S., 'Copy Number Variation Screen Identifies a Rare De Novo Deletion at Chromosome 15q13.1-13.3 in a Child with Language Impairment.'
  PLoS ONE 13 (4) (2015) pp.418-429
  ISSN: 1932-6203
  Abstract A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1–13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.Website 
• Villanueva P, Nudel R, Hoischen A, Fernández MA, Simpson NH, Gilissen C, Reader RH, Jara L, Magdalena Echeverry M, Francks C, Baird G, Conti-Ramsden G, O'Hare A, Bolton PF, Hennessy ER; SLI Consortium., Palomino H, Carvajal-Carmona L, Veltman JA, Cazier JB, De Barbieri Z, Fisher SE, Newbury DF., 'Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment.'
  PLoS Genetics 11 (3) (2015)
  ISSN: 1553-7390 eISSN: 1553-7404
  Abstract Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.Website 
• Moralli D, Nudel R, Chan MT, Green CM, Volpi EV, Benítez-Burraco A, Newbury DF, García-Bellido P., 'Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2.'
  Molecular Cytogenetics 8 (36) (2015)
  ISSN: 1755-8166 eISSN: 1755-8166
  Abstract
  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.
  Website 
• Pettigrew KA, Fajutrao Valles SF, Moll K, Northstone K, Ring S, Pennell C, Wang C, Leavett R, Hayiou-Thomas ME, Thompson P, Simpson NH, Fisher SE; SLI Consortium, Whitehouse AJ, Snowling MJ, Newbury DF, Paracchini S., 'Lack of replication for the myosin-18B association with mathematical ability in independent cohorts'
  Genes, Brain and Behavior 14 (4) (2015) pp.369-376
  ISSN: 1601-1848
  Abstract Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin‐18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome‐wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths‐related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin‐18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin‐18B variant is unlikely to be a main factor contributing to mathematical abilities.Website 
• Simpson NH, Ceroni F, Reader RH, Covill LE, Knight JC; SLI Consortium.,Hennessy ER, Bolton PF, Conti-Ramsden G, O'Hare A, Baird G, Fisher SE, Newbury DF, 'Genome-wide analysis identifies a role for common copy number variants in specific language impairment.'
  European Journal of Human Genetics 23 (2015) pp.1370-1377
  ISSN: 1018-4813 eISSN: 1476-5438
  Abstract An exploratory genome-wide copy number variant (CNV) study was performed in 127 independent cases with specific language impairment (SLI), their first-degree relatives (385 individuals) and 269 population controls. Language-impaired cases showed an increased CNV burden in terms of the average number of events (11.28 vs 10.01, empirical P=0.003), the total length of CNVs (717 vs 513 Kb, empirical P=0.0001), the average CNV size (63.75 vs 51.6 Kb, empirical P=0.0005) and the number of genes spanned (14.29 vs 10.34, empirical P=0.0007) when compared with population controls, suggesting that CNVs may contribute to SLI risk. A similar trend was observed in first-degree relatives regardless of affection status. The increased burden found in our study was not driven by large or de novo events, which have been described as causative in other neurodevelopmental disorders. Nevertheless, de novo CNVs might be important on a case-by-case basis, as indicated by identification of events affecting relevant genes, such as ACTR2 and CSNK1A1, and small events within known micro-deletion/-duplication syndrome regions, such as chr8p23.1. Pathway analysis of the genes present within the CNVs of the independent cases identified significant overrepresentation of acetylcholine binding, cyclic-nucleotide phosphodiesterase activity and MHC proteins as compared with controls. Taken together, our data suggest that the majority of the risk conferred by CNVs in SLI is via common, inherited events within a ‘common disorder–common variant’ model. Therefore the risk conferred by CNVs will depend upon the combination of events inherited (both CNVs and SNPs), the genetic background of the individual and the environmental factors.Website 
• Ceroni F, Simpson NH, Francks C, Baird G, Conti-Ramsden G, Clark A, Bolton PF, Hennessy ER, Donnelly P, Bentley DR, Martin H, IMGSAC, SLI Consortium, WGS500 Consortium, Parr J, Pagnamenta AT, Maestrini E, Bacchelli E, Fisher SE, Newbury DF., 'Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.'
  European Journal of Human Genetics 22 (2014) pp.1165-1171
  ISSN: 1018-4813 eISSN: 1476-5438
  Website 
• Genome-wide screening for DNA variants associated with reading and language traits. Gialluisi A, Newbury DF, Wilcutt EG, Olson RK, DeFries JC, Brandler WM, Pennington BF, Smith SD, Scerri TS, Simpson NH; SLI Consortium, Luciano M, Evans DM, Bates TC, Stein JF, Talcott JB, Monaco AP, Paracchini S, Francks C, Fisher SE., 'Genome-wide screening for DNA variants associated with reading and language traits.'
  Genes, Brain and Behavior 13 (7) (2014) pp.686-701
  ISSN: 1601-1848
  Abstract Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Website 
• Newbury DF, Monaco AP, Paracchini S., 'Reading and language disorders: the importance of both quantity and quality.'
  Genes 5 (2) (2014) pp.285-309
  ISSN: 2073-4425
  Abstract Reading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, only a few genes have been implicated in these traits. Their functional characterization has provided novel insight into the biology of neurodevelopmental disorders. However, the lack of biological markers and clear diagnostic criteria have prevented the collection of the large sample sizes required for well-powered genome-wide screens. One of the main challenges of the field will be to combine careful clinical assessment with high throughput genetic technologies within multidisciplinary collaborations.Website 
• Simpson NH, Addis L, Brandler WM, Slonims V, Clark A, Watson J, Scerri TS, Hennessy ER, Bolton PF, Conti-Ramsden G, Fairfax BP, Knight JC, Stein J, Talcott JB, O'Hare A, Baird G, Paracchini S, Fisher SE, Newbury DF; SLI Consortium., 'Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia.'
  Developmental Medicine and Child Neurology 56 (4) (2014)
  ISSN: 0012-1622 eISSN: 1469-8749
  Abstract
  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.
  Website 
• Nudel R, Simpson NH, Baird G, O'Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER; SLI Consortium, Ring SM, Davey Smith G, Francks C, Paracchini S, Monaco AP, Fisher SE, Newbury DF., 'Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.'
  Genes, Brain and Behavior 13 (4) (2014)
  ISSN: 1601-1848
  Abstract Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome‐wide association study of SLI which included parent‐of‐origin effects and child genotype effects and used 278 families of language‐impaired children. The child genotype effects analysis did not identify significant associations. We found genome‐wide significant paternal parent‐of‐origin effects on chromosome 14q12 (P = 3.74 × 10−8) and suggestive maternal parent‐of‐origin effects on chromosome 5p13 (P = 1.16 × 10−7). A subsequent targeted association of six single‐nucleotide‐polymorphisms (SNPs) on chromosome 5 in 313 language‐impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P = 0.001); as fathers' genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent‐of‐origin effects. The paternally‐associated SNP on chromosome 14 yields a non‐synonymous coding change within the NOP9 gene. This gene encodes an RNA‐binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent‐of‐origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.Website 
• Ceroni F, Sagar A, Simpson NH, Gawthrope AJ, Newbury DF, Pinto D, Francis SM, Tessman DC, Cook EH, Monaco AP, Maestrini E, Pagnamenta AT, Jacob S., 'A deletion involving CD38 and BST1 results in a fusion transcript in a patient with autism and asthma.'
  Research in Autism Spectrum Disorders 7 (2) (2014)
  ISSN: 1750-9467
  Abstract CD38 encodes a ligand in the oxytocin signaling pathway. Some single nucleotide polymorphisms in this gene have been associated with low serum oxytocin levels in autism spectrum disorder (ASD) patients. Oxytocin disruption has been hypothesized to account for features of ASD, including impaired communication and social behavior, based on animal studies. Recent human studies have shown administration of oxytocin improving emotion recognition, promoting social behavior, and improving auditory processing of social stimuli in ASD patients. In addition to its role in oxytocin signaling, CD38 is involved in the regulation of calcium concentration in airway smooth muscle with impairment of CD38 being implicated in airway diseases like asthma. While a number of studies have implicated rare chromosomal deletions and duplications in helping determine genetic risk for autism, there are to our knowledge no reports describing rearrangements involving CD38 or deletions in patients with ASD. Here, we present two sisters diagnosed with autism and with features of regression—previously acquired speech lost in the second year of life. The younger sister, who also had asthma, inherited a maternal deletion of 4p15.32 that results in a BST1‐CD38 fusion transcript. Their mother's deletion was mosaic and she was not affected. Although further work is required to assess functional consequences of the fusion transcript, we hypothesize that the proband's deletion may have served as a risk factor for autism that, when combined with other susceptibility variants, resulted in a more severe presentation than her sister. Autism Res 2014, 7: 254–263Website 
• Nudel R, Simpson NH, Baird G, O'Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER; SLI Consortium, Monaco AP, Knight JC, Winney B, Fisher SE, Newbury DF., 'Associations of HLA alleles with specific language impairment.'
  Journal of Neurodevelopmental Disorders 6 (1) (2014)
  ISSN: 1866-1947
  Abstract
  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.
  Website 
• Nudel R, Newbury DF., 'FOXP2'
  Wiley Interdisciplinary Reviews: Cognitive Science 4 (2013) pp.547-560
  ISSN: 1939-5078
  Abstract
  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
  Website 

Book chapters

• Mountford H, Newbury DF, 'The Genetics of Language Acquisition' in J.S. Horst and J von Koss Torkildsen (ed.), The International Handbook of Language Acquisition, Routledge (2019)
  ISBN: 9781138087217 eISBN: 9781315110622
  Abstract

  This chapter focuses on the understanding of the role of genetics in language and explores how genetics contribute to language, and shows how new genetic techniques can offer inroads into the molecular basis of language acquisition. It discusses some of the key findings of gene x environment studies and provides a snapshot of the understanding in the field, considering some of the limitations of the type of study design. The chapter describes the field of play in the genetics of language acquisition and explains the heritability of language and the role of family and twin studies in the understanding of language. It also explores the inheritance mechanisms that are implicated in language development. The chapter considers how modern DNA sequencing approaches are revolutionizing the field of language genetics. Heritability studies have provided many key insights into the genetics of both language acquisition and language disorders. Insights into mechanisms can also come from the opposite end of the language ability spectrum.
  

  Website 
• Nudel R, Ceroni F, Simpson N, Newbury DF, 'The genetics of specific language impairment (SLI)' in Stavrakaki S (ed.), Specific Language Impairment, John Benjamins Publishing Company (2015)
  ISBN: 9789027253217
  Website 

Areas of expertise

Gene mapping (linkage, association, sequencing)

Speech and language disorders

Neurodevelopmental disorders

Membership of professional bodies

MRC College of Reviewers for the Newton Fund.

International Scientific Advisory board for the University of Connecticut

Scientific Advisor for the Press and Information Office at the University of Oxford.

Conferences

Other experience

University Reseach Lecturer at Oxford University

MRC career Development Fellow

Junior Research Fellow, St Johns College

Tutorial Fellow, Somerville College

Other publicity

Further information

See http://www.well.ox.ac.uk/webcasts-podcasts for podcasts and interviews

@diannenewbury