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Department of Biological and Medical Sciences
Faculty of Health and Life Sciences
Gipsy Lane, Sinclair, S306b
I am a senior lecturer on the MSc Medical Genetics and Genomics programme and I am principal investigator of a research lab in the Department of Health and Life Sciences.
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
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.
Hayley Mountford (post-doc) p0083144
Lidiya Nevedska (PhD student) 16034238
Nuala Simpson (post-doc) p0084691
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
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.
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 (<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.
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.
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.
Gene mapping (linkage, association, sequencing)
Speech and language disorders
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.
University Reseach Lecturer at Oxford University
MRC career Development Fellow
Junior Research Fellow, St Johns College
Tutorial Fellow, Somerville College
See http://www.well.ox.ac.uk/webcasts-podcasts for podcasts and interviews