Department of Biological and Medical Sciences


  • On this page, you will find abstracts and supporting material for presentations given by the Newbury group at recent conferences.

    Society for the Neurobiology of Language 2019

    Hayley presented a poster at the SNL in Helsinki. This work is funded by a Leverhulme Project grant.

    A17 - gnikaepS sdrawkcaB: from extreme language traits to mechanisms

    Hayley Mountford, Stefan Prekovic, Nayeli Gonzalez-Gomez, Isabel Bermudez-Diaz, Dianne Newbury

    Abstract: Language ability is highly heritable and therefore has a strong genetic component. Despite decades of study, we understand little of the genetic and molecular mechanisms which underpin typical language development. Insights into the genetic basis of language have primarily come from the study of language disorders, implicating over thirty-five genes in language function. A key assumption being that the genes and mechanisms contributing to language disorders are the same factors that underpin typical language development. An alternative approach is offered through the neurological and genetic characterisation of individuals with extreme ability, rather than disability. We leverage this approach to better understand mechanisms relevant to typical language development. Here we report on a novel molecular mechanism identified through the investigation of an extreme language trait – the ability to speak backwards. We identified a father and daughter who can rapidly and accurately reverse phonemes to speak backwards fluently. We showed that this remarkable phenotype is underpinned by exceptional working memory. Using fMRI, we established that their extreme ability is supported by visual semantic loops within the left fusiform gyrus. Our analysis of this family identified a novel coding variant (c.G262A, p.G88R) in the gene RIC3; a chaperone of the α7 subunit of the nicotinic acetylcholine receptor (nAChR) which is critical for cholinergic synaptic transmission. The α7 nAChR is one of the most abundant receptors in the mammalian brain and plays a pivotal role in brain development. Traditionally, these receptors are associated with neuropsychiatric disorders such as schizophrenia and Alzheimer’s disease. Through electrophysiological studies using Xenopus laevis oocytes as a model for nAChR activity, we detected a positive functional effect of the RIC3 variant upon cholinergic synaptic transmission. This provides direct evidence for the role of RIC3 as a nAChR chaperone, and of its mediatory role in memoryrelated circuits. Expanding on these findings, we are currently recruiting and testing additional participants with the ability to speak backwards. Preliminary assessment suggests that this trait is heterogeneous, and not necessarily driven by superior working memory in all cases. This indicates that backwards speech is a complex trait with many neurological and genetic drivers likely to play a role. The successful identification of RIC3 and the characterisation of its role in working memory demonstrates the utility of extreme traits to uncover novel mechanisms that underpin language. By expanding this successful approach to a wider cohort of backwards speakers, we aim to characterise the cognitive processes that underpin backwards speech and use this to reveal novel neuromolecular pathways involved in language acquisition.  

    European Society of Human Genetics 2019

    Lidiya presented a poster at the ESHG in Gothenberg.

    P02.06D - Multi-level evidence of an allelic hierarchy of USH2A variants; hearing loss, auditory processing and speech/language outcomes

    P.A. Perrino, L. Nedevska, R. Reader, A. Hill, A.R. Rendall, H.S. Mountford, A.N. Buscarello, N. Lahiri, A. Saggar, R.H. Fitch, D.F. Newbury.
    Introduction: Hearing and auditory processing are fundamental to language development. Genetic mechanisms that alter these processes may therefore have secondary effects on emergent language. In this work, we consider variations across the USH2A gene and characterise an allelic hierarchy associated with alternate and distinct clinical manifestations including Auditory Processing Disorder (APD), Developmental Language Disorder (DLD) and Usher syndrome.
    Materials and Methods: This investigation combines whole genome sequencing data from a family affected by a severe form of APD and speech dysarthria with genetic characterisation of two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. To compliment human findings, a mouse model with a genetic knockout of the rodent homolog Ush2a was assessed for auditory processing and vocalizations.
    Results: Combined human and mouse results show: (1) heterozygous USH2A disruptions lead to impaired low-frequency sound perception; (2) low-level hearing impairments caused by heterozygous disruption of Ush2a associate with persistent higher-order acoustic processing deficits and altered vocalizations in mice; and (3) risk variants of USH2A combined with altered low-frequency hearing thresholds lead to significantly worse language outcomes in humans.
    Conclusions: We identify a complex, interactive genetic mechanism under which variants in USH2A contribute to low-frequency hearing loss and alter higher-order auditory processing increasing the risk of language disorder. Since these variants are found in 0.85% of the population, we recommend comprehensive genetic screening to enable the early identification of carrier individuals alongside specific assessment of low-frequency hearing in individuals at risk.

    Society for the Scientific Study of Reading 2018

    Carol presented a talk at the SSSR in Southampton

    A randomized controlled trial to investigate the causes and correlates of poor reading in an isolated population

    First Author/:Carol Mesa -- Department of Experimental Psychology University of Oxford
    Purpose: This study aimed to raise the literacy attainments of Spanish-speaking children residing in a geographically isolated region of Chile.
    Method: Participants in this study came from a rural and isolated community that has a high incidence of language and learning disorders (Villanueva et al 2008). Eligible children were allocated to the intervention (n= 34) or waiting control group (n =34) with minimization on language measures. Children in the intervention group received a 30-week intervention, adapted from effective UK interventions and adapted to cultural norms; it comprised training in phonological awareness, emergent reading skills, reciprocal reading, vocabulary and narrative, adjusted to the skill levels of the pupils as the intervention progressed.
    Results: We will compare the outcomes of children receiving the intervention with those in the waiting control group on composite measures of reading, language and reading comprehension at post-test and 6 months later at follow-up (at which time the control group have also been treated), and assess the predictors of response to intervention in both groups, including the effects of dosage.
    Conclusions: Despite the challenges of implementing interventions in remote communities, findings support the importance of oral language and phonological skills to reading development.

    European Society of Human Genetics 2018

    Hayley presented a poster at the ESHG in Milan

    P18.02B / B - Investigating the population structure of Robinson Crusoe Island, Chile

    H. S. Mountford, P. Villanueva, L. Jara, M. A. Fernandez, Z. De Barbieri, L. Carvajal-Carmona, J. Cazier, D. F. Newbury; 
    Abstract / Summary:  
    Robinson Crusoe (RCI) is a geographically and socially isolated island located 670km west of San Antonio, Chile. It was founded in 1876 by a group of eight founder families. It is now home to over 800 inhabitants, most of whom are descended from the original founder families. The geographical isolation of RCI means few outsiders have migrated to the island. As a result, islanders share a high degree of consanguinity (14.9%), and most islander unions are at least second cousins (Villanueva et al 2014).
    RCI islanders show an exceptionally high occurrence rate of developmental language disorder, 10-fold the rate seen in mainland Chile. Near complete islander genealogical records have shown that 90% of affected children are direct descendants of a pair of original founder brothers, who likely carried a susceptibility variant for language disorders (Villanueva et al 2014).
    To understand the genetic contribution to developmental language disorder on RCI, we have investigated the underlying population structure of the islanders. Extensive pedigree data suggest the current islander population are of recently admixed European and Chilean backgrounds. Recent studies have shown a higher proportion of indigenous South American ancestry in the mainland Chilean population than previously thought (Lorenzo-Bermejo et al 2017), and this may therefore be directly relevant to the RCI population.
    Using high density genome-wide SNP genotyping data from 154 islanders, and whole genome sequencing from 24 of the most distantly related islanders, we have performed the first in-depth genetic analysis of the population structure of RCI.

    British Dyslexia Association Conference 2018

    Carol presented a talk at the BDA in Telford entitled "A Language and Reading Intervention for a Rural and Isolated Population" Carol Mesa, Margaret Snowling ; Charles Hulme ; Marysia Nash; Zulema de Barbieri ; Pia Villanueva ; María Angélica Fernández; Dianne Newbury 

    Society for the Scientific Study of Reading 2017

    Carol presented a talk at the SSSR in Nova Scotia

    A Language and Reading Intervention for a Rural and Isolated Population

    Carol Mesa, Margaret Snowling ; Charles Hulme ; Marysia Nash; Zulema de Barbieri ; Pia Villanueva ; María Angélica Fernández; Dianne Newbury
    Abstract / Summary: 
    Purpose: The purpose of this study was to examine the effects of a language and reading intervention on population that is culturally and geographically isolated from mainland Chile.
    Method: Participants in this study came from a rural and isolated community in Chile that has been identified to have a high incidence of language and learning disorders (Villanueva et. al., 2008). Children whose parents consented (aged 4 years 5 months to 14 years 7 months) were screened on two language measures (expressive vocabulary and recalling sentences). They were then randomly allocated to the experimental (n= 34) or waiting control group (n =34) following minimization on language measures. Children in the experimental group received a 30-week program based on interventions previously evaluated as effective and adapted to cultural norms. The intervention was aimed to foster code-related skills, reading strategies, and oral language skills.
    Results: ANCOVA controlling for baseline scores will be used to analyse pre- and post—intervention differences in primary (reading) and secondary (language) outcomes. We hypothesized that children receiving the intervention (experimental group) would show significantly larger gains than children who did not initially receive the intervention (waiting control group) in reading and language measures.
    Conclusions: Findings will inform future language and literacy programs aimed at fostering language and literacy skills in populations that are culturally and linguistically diverse. The challenges of implementing interventions in remote communities will be discussed.

    Nicotinic Acetylcholine Receptor Conference 2017

    Fabiola presented a talk describing our work on the backwards speech project at the nAChR meeting in Crete. She won a Young Scientist Travel Award for her presentation.

    RIC3 mutation enhances functional expression of α7 nicotinic receptors

    Fabiola Ceroni, Hayley Mountford, Stefan Prekovic, Lidiya Nedevska, Dianne F Newbury and Isabel Bermudez

    The α7 nicotinic acetylcholine receptor is one of the most abundant receptors in the mammalian brain and plays a pivotal role in brain development. Traditionally, these receptors are associated with neuropsychiatric disorders. More recent studies indicate that they may also be involved in peripheral inflammatory processes. As such, the understanding of the function and regulation of these receptors may have important implications for a growing range of disorders including Alzheimers, schizophrenia and septicemia. We recently identified a novel coding mutation (NM_024557:exon2:c.G262A:p.G88R) in the RIC3 gene which was associated with the ability to spontaneously and accurately speak backwards. The RIC3 protein is a chaperone of α7 nAChR and is thought to act as a mediator of folding and/or assembly processes. RIC3 enhances α7-mediated whole-cell current amplitudes of mammalian clonal cells or Xenopusoocytes expressing heterologusly α7 receptors. Since the backwards speech process loads heavily upon working memory, we sought to characterise the effect of this mutation upon the function of α7 nicotinic receptor function. Wild-type and mutated RIC3 genes were cloned and co-expressed in Xenopus oocytes with α7 or α4β2 nAChR expression vectors. Two electrode voltage clamp (TEVC) indicated that, as expected, currents were minimal in the presence of α7 alone. Co-expression of wild-type RIC3 led increased maximal current in the presence of acetylcholine validating the mediatory role of this protein. Furthermore, we found this response was significantly augmented in the presence of mutated RIC3. No shift in the acetylcholine concentration response curve was apparent. The altered response was found to be specific to α7 nAChRs; the mutated RIC3 gene did not change the functional expression of α4β2 receptors. As such, our results support a key role for RIC3 and α7 in cognition and specifically verbal short-term memory. We suggest that RIC3 may represent a novel target for the modulation of cholinergenic synaptic transmission and highlight RIC3 as a key player in a7-dependent brain behaviour.

    This research was supported by the central research fund of Oxford Brookes University.

    British Neuroscience Association 2017

    I presented at a symposium as part of the British Neuroscience Association meeting in Birmingham in 2017. This session was funded by the Genetics Society.

    Symposium 17: Genetics of language disorders: from gene mapping to biological mechanisms

    Supported by The Genetics Society. Tuesday 11th April, 13:20 – 15:00
    Current genomic technologies offer an unprecedented resolution to map common and rare variants underlying human diseases. The use of genomic information applied to the field of literacy and language genetics, however, still faces significant challenges. A main difficulty resides in the definition of the phenotype which cannot be measured under universal and homogenous criteria, especially across different countries because of its dependence on the spoken (and written) language. Nevertheless, significant progress has been made both in identifying novel genes for these complex traits and in dissecting their biological function.
    This symposium brings together four internationally recognised researchers who have significantly contributed to recent advances in this field. We will discuss the importance of phenotype definition for gene identification through genetic screenings by quantitative GWAS and next generation sequencing. Gene mapping is only the initial step and genetic associations require to be followed up by functional studies to understand their relevance to a phenotype. However, another significant challenge is to identify suitable biological models to study the role of these genes during neurodevelopment.
    The presentations will discuss the use of stem cells, zebrafish, mice and bats to study of candidate genes for complex traits contribute to neuronal function and neurodevelopment. An intriguing finding in the area is that of an unexpected role of dyslexia candidate genes in cilia biology which is advancing our understanding of cellular mechanisms, e.g. neuronal migration, implicated in the early phases of brain development. Talks will therefore cover the route which goes from clinical and phenotypic assessment to the study of biological mechanisms.
    The findings and methodology presented at this symposium will be relevant to the field of complex cognitive trait genetics and psychiatric disorders, going well beyond the context of language-related conditions.

    Chairs: Dr Silvia Paracchini (St Andrews) and Dr Dianne Newbury (Oxford)
    Speaker 1: Professor Tim Bates (University of Edinburgh)
    'Genetic associations with variation in reading and language ability: present results and future directions'
    Speaker 2: Dr Dianne Newbury (University of Oxford)
    'Using extreme traits to identify genetic contributions to speech and language disorders'
    Speaker 3: Dr Silvia Paracchini (University of St Andrews)
    'Dyslexia and cilia biology: a new link between cognition and brain asymmetries?'
    Speaker 4: Dr Sonja Vernes (Max Planck Institute, The Netherlands)
    'Model systems to understand language disorders: FOXP2 and beyond'

    European Society of Human Genetics 2016

    Two young investigators from our lab presented at the European Society of Human Genetics in Barcelona.

    Fabiola Ceroni presented a poster describing her findings in a case study of Childhood Disintegrative Disorder (CDD), a rare and devastating form of autism with regression.

    Stefan Prekovic presented a poster describing his characterisation of a family with the rare ability to speak backwards. This work formed the basis of a paper in Scientific Reports earlier this year.

    Abstracts for both posters are given below

    Title: P09.045A - Case report: exome sequencing of a family with childhood disintegrative disorder.
    Keywords: Childhood disintegrative disorder; PCM1; ALMS1
    Authors: F. Ceroni1, M. Absoud2, G. Baird2, A. Velayos-Baeza1, D. Newbury1;
    1Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom, 2Guy's & St Thomas’ NHS Foundation Trust, London, United Kingdom.
    Abstract: Childhood disintegrative disorder (CDD) is a very rare but devastating neurodevelopmental condition characterised by rapid and severe decline in developmental skills (communication, play, self-care, cognition) in children with apparently normal previous development for the first 2 years of life. The regression results in significant long-term impairments in social communication skills, similar to features of Autism Spectrum Disorder (ASD) with severe intellectual disability. Extensive neurometabolic investigations usually do not reveal an underlying aetiology. We report an exome sequencing study of a family with two affected children and neurotypical parents. Pathway analyses of rare and potentially damaging variants highlighted two variants in genes involved in intracellular trafficking and recruitment of proteins to the centrosome: both children carry a maternal stop codon in PCM1 (NP_006188, p.E1912X) and a paternal nonsynonymous change in ALMS1 (NP_055935, p.S763N). PCM1 is an essential component of the centriolar satellites and interacts with several proteins, including DISC1 (disrupted in schizophrenia 1) and BBS4 (Bardet-Biedl Syndrome 4). Mutations in ALMS1 can cause Alström Syndrome, a rare recessive multi-system ciliopathy, closely related to the Bardet-Biedl Syndrome (BBS). The biological functions of ALMS1 are still being elucidated, but roles in cilium function and maintenance, intracellular trafficking, signaling pathways and cell cycle regulation have been suggested. Although the functional interaction between ALMS1 and PCM1 needs to be further investigated, the participation of the two proteins to the same cellular network, which has been previously implicated in other neurodevelopmental disorders, led us to hypothesize a possible compound effect of the two identified variants

    Title: P09.143 - Multidisciplinary investigation of backward-speech trait suggests a link between RIC3, RIPK1, ZBED5 and working memory
    Keywords: speech; working memory; RIC3
    Authors: S. Prekovic1, D. Filipović Đurđević2,3, G. Csifcsák4, O. Sveljo5,6, O. Stojković7, F. Ceroni8, D. F. Newbury8;
    1Faculty of Medicine, KU Leuven, Leuven, Belgium, 2Faculty of Philosophy, University of Novi Sad, Novi Sad, Serbia, 3Faculty of Philosophy, University of Belgrade, Belgrade, Serbia, 4Institute of Psychology, Faculty of Arts, University of Szeged, Szeged, Hungary, 5Diagnostic Imaging Center, Oncology Institute of Vojvodina, Sremska Kamenica, Serbia, 6Faculty of Technical Sciences, University of Novi Sad, Novi Sad, Serbia, 7Faculty of Medicine, University of Belgrade, Belgrade, Serbia, 8Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom.
    Abstract: Introduction: Working memory is essential for the development of many language-related traits. It has been suggested that the rare trait of backward-speaking is linked to working memory. This trait is described as an ability to spontaneously and accurately reverse words. Here we describe individuals (the father and daughter) from a Serbian family who have the ability to speak backward voluntarily.
    Materials and Methods: We employed behavioral tests to describe the trait and neuroimaging (EEG and fMRI) to study the neural processing behind backward-speech. Moreover, we investigated coding sequence changes through exome sequencing and copy number variations using SNP array data in this family.
    Results: Behavioral data suggests that backward-speech loads heavily upon working memory. Event-related potentials above the frontal lobe are affected by word reversal and the maintenance of backward-words in working memory. fMRI revealed that the left fusiform gyrus may facilitate backward-speech in the daughter. Exome sequencing identified three novel coding variants of potential significance in the RIC3, RIPK1 and ZBED5 genes.
    Conclusions: Our data suggest that in the daughter, backward-speech is afforded by an extraordinary working memory capacity. We hypothesize 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 processes may be mediated by a genetic mutation in the RIC3 gene which encodes a chaperone for nicotinic acetylcholine receptors.
    This research was supported by grants from MSTD (179006, 179033 and 175093), NBRP (KTIA_13_NAP-A-II/20), and MRC (G1000569/1 and MR/J003719/1).

    Oxford Neuroscience Symposium 2016

    In March 2016, Hayley Mountford presented a poster describing her work at the Oxford Neuroscience Symposium.

    Confer Do Genes (ever) Determine our Mental Health? 2016

    I presented at a Confer debate in June 2016. You can download a pdf of my presentation at Confer here.

    The nature-versus-nurture debate is always of great fascination to anyone wishing to discover the means by which we can best facilitate growth and health. Today, now that discussion is powered by the findings of the two human genome projects, we should have much better evidence for understanding the proportional roles of environment-versus-biological heredity. Of obvious great interest to all those concerned with health is how to get a better understanding of the major illnesses and their aetiology - particularly those with clear biological mechanisms. But what does research tell us about psychological issues? Are they influenced by DNA? And can they be reduced to physiology? Where do personality, emotional disposition or disorders of mental health originate? This day invites three presenters to examine the evidence.

    Building the Brain, Genetics Society Conference at the Royal Society, London 2015

    I presented an overview of the genetics of speech and language disorders at the Building the Brain conference in December 2015.

    Genetic contributions to Specific Language Impairment (SLI).

    Disorders of speech and language are common in childhood and presumably arise from subtle disturbances during brain development. Nonetheless, we have little understanding as to the underlying pathology of this group of disorders. They are highly heterogeneous and in the majority of cases are genetically complex. In this talk, I will provide an overview of genetic studies of speech and language disorders. I will discuss how increases in sample sizes and the application of new technologies may highlight conserved mechanisms of language development providing a better understanding of the biological contributions to these disorders.

    American Society of Human Genetics 2015

    We were co-authors on a paper presented at the American Society of Human Genetics by Heather Cordell's group at the University of Newcastle. The poster described the use of haplotype information to increase power to detect parent of origin effects. Details of the study and methods can be found in an American Journal of Human Genetics paper. This work was also presented at the International Genetic Epidemiology Society in October 2015. An abstract for the poster is below:

    Increased power for detection of parent-of-origin effects via the use of haplotype estimation

    Richard Howey (1), Chrysovalanto Mamasoula (1,2), Ana Töpf (1), Ron Nudel (3), Dianne F. Newbury (3), Simon E. Fisher (4,5), Judith A. Goodship (1), Bernard D. Keavney (1,6), Heather J. Cordell (1)

    1 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK

    2 Institute of Health and Society, Newcastle University, Newcastle upon Tyne, NE2 4AX, UK

    3 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK

    4 Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands

    5 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands

    6 Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9NT, UK

    Parent-of-origin (or imprinting) effects relate to the situation where traits are influenced by the allele inherited from only one parent, with the allele from the other parent having little or no effect. Given SNP genotype data from case/parent trios, the parent-of-origin of each allele in the offspring can often be deduced unambiguously; however this is not true when all three individuals are heterozygous. Most existing methods for investigating parent-of-origin effects operate on a SNP by SNP basis and either perform some sort of “averaging" over the possible parental transmissions or else discard ambiguous trios. If the correct parent-of-origin at a SNP could be determined, this would provide extra information and increase the power to detect effects of imprinting. We propose making use of the surrounding SNP information, via haplotype estimation, to improve estimation of parent-of-origin at a test SNP for case/parent trios, case/mother duos and case/father duos. This extra information is then used in a multinomial modelling approach to estimate parent-of-origin effects at the test SNP. We show through computer simulations that our approach has increased power over previous approaches, particularly when the data consist only of duos. We apply our method to two real data sets and find a decrease in significance of p-values in genomic regions previously thought to possibly harbour imprinting effects, thus weakening the evidence that such effects actually exist in these regions, although some regions remained more significant than expected.

    Attention, Brain and Cognitive Development 2015

    I presented a poster at the attention, brain and development seminar in Oxford (June 22nd 2015) describing our findings regarding season of birth effects in the ALSPAC cohort. This work was completed by Laura Covill, a gap year student in our lab. The abstract is below:

    Relationship Between Season of Birth And Educational Attainment in ALPSAC Support Existence of Relative Age Effect

    DF Newbury, LE Covill, NH Simpson, G Davey Smith & S Paracchini

    It has been suggested that season-of-birth can affect scholastic achievement and the chances of being diagnosed with a neurodevelopmental disorder. In this study, we investigate the relationship between season of birth, the presence of neurodevelopmental disorders, and scholastic attainment in children, in the ALSPAC child population cohort. We find that, as a group, Summer-born children perform better in tests of IQ, reading and spelling proficiency. Despite this, Summer-born children are more likely to be diagnosed with specific learning disorders, particularly those centred on reading and writing ability, and achieve fewer GCSEs than their counterparts. These effects are small in real terms but consistent across time points. Our data show that Summer-born children are at a disadvantage when directly compared to their classmates in subjective examinations, which do not adjust for absolute age. We suggest that such disadvantages could be offset by the use of age-normalised testing in state examinations.

    European Society of Human Genetics 2015

    We were co-authors on two presentations at the European Society of Human Genetics in June 2015.

    Sameuelle Fajutrao Valles described her work on associtions across MYO18B and dyscalculia and Robert Shore described his work on the PCSK6 gene. Both researchers are from Silvia Paracchini's lab at the University of St Andrews. Abstracts are below.

    Title: PS08.15 - Myosin-18B and mathematical ability in independent cohorts: lack of replication in independent cohorts
    Keywords: dyscalculia; myosin-18B; replication
    Authors: S. Fajutrao Valles1, K. A. Pettigrew1, K. Moll2, K. Northstone3, S. Ring3, C. Pennell4, C. Wang4, R. Leavett5, M. E. Hayiou-Thomas5, P. Thompson6, N. H. Simpson7, S. E. Fisher8, The SLI Consortium, A. J. O. Whitehouse9, M. J. Snowling10, D. F. Newbury10, S. Paracchini1;
    1School of Medicine, University of St Andrews, St Andrews, United Kingdom, 2Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany, 3School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom, 4School of Women's and Infants' Health, University of Western Australia, Crawley, Australia, 5Department of Psychology, University of York, York, United Kingdom, 6Department of Experimental Psychology, University of Oxford, St Andrews, United Kingdom, 7Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 8Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands, 9Telethon Kids Institute, University of Western Australia, Crawley, Australia, 10St. John's College, University of Oxford, Oxford, United Kingdom.
    Abstract: Dyscalculia (or mathematical ability) is a condition where mathematical ability is severely impaired. Twin studies suggest that it is partly caused 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. However, this association has not been replicated before. We conducted a replication analysis in different cohorts characterised with maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC) (N=3819), which was adequately powered for this analysis. We tested additional cohorts including the York Cohort (N=291), the Specific Language Impairment Consortium (SLIC) (N=367) and the Raine Cohort (N=667). Cohorts were stratified for a definition of dyslexia where 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 then suggest that the Myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities.
    SP is a Royal Society University Research Fellow. The study in the ALSPAC cohort was supported by [Grant number G0800523/8647] and [Grant ref:102215/2/13/2]. The Raine study was supported by [Grant 572613] and [Grant MOP 82893]. The work in the University of Oxford was supported by [Grant number 1004065] [G1000569/1 and MR/J003719/1] and [090532/Z/09/Z]. The study in the SLIC cohort was supported by [060774 and 076566].

    Title: PS09.097 - The PCSK6 intronic region associated with handedness controls expression of a novel shorter isoform
    Keywords: PCSK6; Handedness; Dyslexia
    Authors: R. J. Shore1, K. Pettigrew1, R. Diaz1, Y. Xu1, E. Wootton1, L. Covill2, W. Brandler2, J. B. Talcott3, D. F. Newbury2, A. Monaco2, J. Stein4, S. Paracchini1;
    1School of Medicine, University of St Andrews, St Andrews, United Kingdom, 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 3School of Life and Health Sciences, Aston University, Birmingham, United Kingdom, 4Dept of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.
    Abstract: We recently reported the first gene, PCSK6, associated with handedness at genome-wide significance level (P< 0.5*10-8, Brandler et al. 2013). A Variable Number Tandem Repeat (VNTR) within the same PCSK6 locus has been found to be associated with degree of handedness in an independent study (Arning et al. 2013). Interestingly, PCSK6 is known to activate NODAL, a morphogen involved in a highly conserved pathway known to regulate left/right body axis determination. Our previous data suggest these pathways controlling development of LR asymmetry in the body are reused for brain midline development, which in turn influence functional asymmetries such as handedness (Brandler and Paracchini 2014). All previous most significant associations fall within a linkage disequilibrium (LD) block containing a secondary promoter our data show to be bidirectional in nature and controlling transcription of both a novel PCSK6 isoform and a long non-coding antisense RNA. Taking forward previous GWAS findings, we have conducted a detailed functional analysis using a combination of further genetic analysis, in-silico predictions, and molecular assays. Our functional studies support an allele-specific effect on transcription factor binding affinity for a previous top-associated SNP rs11855425 however our genetic data could not find any evidence supporting a VNTR role. With this study we have dissected the molecular mechanisms underlying the PCSK6 association with handedness, indicating the regulatory effect the region has on specific RNA isoforms. Future work will focus on understanding the function of the novel shorter PCSK6 isoform and confirming the identity and role of the transcription factors binding at the secondary promoter.Neurodys018696, WT090532/Z/09/Z, MRCG090074791070, G1000569/1 and MR/J003719/1.

    British Dyslexia Association 2014

    I presented a powerpoint presentation as part of a symposium entitled "Genetic and environmental influences on reading (dis)ability" at the British Dyslexia Association meeting in Guildford (27th March 2014). My abstract is below.


    Specific Language Impairment (SLI) is defined as a substantial deficit in oral language skills despite adequate intelligence and opportunity. This common childhood condition has a high level of comorbidity with the written language disorder, developmental dyslexia and both show evidence for the existence of strong genetic contributions. Using genetic studies of individuals with speech and language impairments, we have identified common variants and structural rearrangements which may contribute to susceptibility to SLI. We have investigated variations across SLI and dyslexia candidate genes in groups of children affected by oral or written language disorders and find evidence for the existence of complex genetic relationships between these disorders.

    Celebrating a century of international collaboration - MRC - 2013

    We won first prize in an MRC competition for Internation collaborative research. My Chilean collaborator Pia Villaneuva and I presented a poster at the Royal society in London as part of this competition.

    European Society of Human Genetics 2013

    Title: P06.47 - Increased prevalence of sex chromosome aneuploidies in Specific Language Impairment and Dyslexia.
    Keywords: specific language impairment; dyslexia; sex chromosome aneuploidy
    Authors: N. H. Simpson1, L. Addis2, W. M. Brandler1, V. Slonims3, A. Clark4, J. Watson4, T. S. Scerri5, J. Stein6, J. B. Talcott7, G. Conti-Ramsden8, A. O'Hare9, G. Baird3, J. C. Knight1, S. Paracchini10, S. E. Fisher11,12, D. F. Newbury1, S. L. I. Consortium1;
    1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 2Institute of Psychiatry, London, United Kingdom, 3Newcomen Centre, Guy’s Hospital, London, United Kingdom, 4Queen Margaret University, Edinburgh, United Kingdom, 5The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 6University of Oxford, Oxford, United Kingdom, 7Aston University, Birmingham, United Kingdom, 8University of Manchester, Manchester, United Kingdom, 9University of Edinburgh, Edinburgh, United Kingdom, 10University of St Andrews, St Andrews, United Kingdom, 11Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands, 12Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
    Abstract: Specific language impairment (SLI) and dyslexia are developmental disorders exhibiting deficits of spoken (SLI) or written (dyslexia) language in the absence of comorbid neurological deficits, despite adequate intelligence and education. Sex chromosome aneuploidies increase the risk of spoken or written language disorders but, compared to other developmental disorders, e.g. autism, individuals with SLI or dyslexia do not routinely undergo cytogenetic analysis.
    To assess the frequency of sex chromosome aneuploidies within individuals with SLI or dyslexia, genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with SLI referred to a child development centre (87 probands), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands) and a set of individuals with dyslexia (310 probands).
    In the clinical SLI cohort, three abnormal karyotypic results were identified in probands, representing a proband yield of 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 aberrations 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 proposed XO/XY mosaic karyotype were identified.
    The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.1%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems, enabling therapies associated with these sex chromosome abnormalities to be implemented more promptly.

    Poster presentation [ pdf]

    Title: P06.48 - Identification of a genomic homozygous deletion of ZNF277 in a child with SLI
    Keywords: Specific Language Impairment (SLI); microdeletion; AUTS1
    Authors: F. Ceroni1, N. H. Simpson2, C. Francks3,4, G. Baird5, G. Conti-Ramsden6, A. E. O'Hare7, E. Maestrini1, E. Bacchelli1, S. E. Fisher3,4, D. F. Newbury2, I. M.G.S.A.C1,2, S. L. I. Consortium2;
    1Dipartimento di Farmacia e Biotecnologie, University of Bologna, Bologna, Italy, 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 3Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands, 4Donders Institute for Brain, Cognition & Behaviour, Nijmegen, Netherlands, 5Guy's & St Thomas NHS Foundation Trust, Newcomen Children's Neurosciences Centre, St Thomas' Hospital, London, United Kingdom, 6School of Psychological Sciences, The University of Manchester, Manchester, United Kingdom, 7Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom.
    Abstract: Specific language impairment (SLI) is a common neurodevelopmental disorder in which language abilities are below age expectations, in the absence of explanatory environmental or medical conditions, such as hearing loss, intellectual disability or autism. SLI affects 3-7% of English-speaking pre-school children. During a genome-wide CNV scan using a multi-algorithm approach, we identified a homozygous deletion of 21,379bp in the ZNF277 gene, overlapping exon 5, in an individual with severe receptive and expressive SLI. This deletion was of particular interest as it falls within the AUTS1 region of linkage to autism. ZNF277 flanks the DOCK4 and IMMP2L genes, which have been suggested to play a role in autistic spectrum disorders (ASD). We therefore screened cohorts of children with SLI or ASD and control subjects for the presence of ZNF277 deletions. We observed an increased frequency of ZNF277deletions in probands with SLI (6/318, 1.9%) compared to both probands with ASD (1/253, 0.4%) and independent controls (2/224, 0.8%). We performed quantitative PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in lymphoblastoid cell lines carrying either a DOCK4 microdeletion or a ZNF277 microdeletion. We found that, while ZNF277 microdeletions affect the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Similarly, DOCK4 microdeletions do not affect the expression levels of ZNF277. Given these findings, we postulate that ZNF277microdeletions may contribute to the risk of speech and language impairments in a manner that is independent of the autism risks previously described in this region.

    Poster presentation

    Behavior Genetics Association 2012

    Exome sequencing of an isolated Chilean population affected by Specific Language Impairment (SLI).
    D. F. Newbury1, A. Hoischen2, R. Nudel1, C. Gilissen2, L. Carvajal-Carmona1,3, M. M. Echeverry3, L. Jara4, Z. De Barbieri5, H. M. Palomino6, M. A. Fernández5, H. Palomino6, J. Veltman2, A. P. Monaco1, P. Villanueva4,5,6, S. E. Fisher1,7

    1) Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom;
    2) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;
    3) Department of Biology, University of Tolima, Tolima, Colombia;
    4) Human Genetics Program, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile;
    5) School of Speech and Hearing Therapy, Faculty of Medicine, University of Chile, Santiago, Chile;
    6) Department of Child and Dental Maxillary Orthopedics, Faculty of Dentistry, University of Chile, Santiago, Chile;
    7) Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

    Speech and language impairments that are a primary deficit and have no obvious cause (e.g. a comorbid neurological disorder like autism) are diagnosed as Specific Language Impairment (SLI). SLI affects 5-8% of preschool children and represents a lifelong disability associated with an increased risk of behavioural disorders, social problems and literacy deficits. SLI is highly heritable and twin studies indicate a strong genetic basis. Nonetheless, the underlying genetic mechanisms are expected to be multifactorial and, to date, only three risk variants have been identified. One way to increase the power to detect contributory genetic factors is to study isolated populations derived from relatively recent shared ancestors (founder populations). In 2008, Villanueva described a founder population with a particularly high incidence of SLI (10 times that expected). They inhabit the Robinson Crusoe Island, which lies 677km to the west of Chileand was colonised in the late 19th century by 8 European and Amerindian families. 77% of the current island population have a colonising surname and 14% of marriages involve consanguineous unions. More than 80% of language impaired individuals can be traced to a pair of founder brothers. This population thus has a short (5-generations) and well-documented history and represents a unique resource which could make valuable contributions to the elucidation of genetic mechanisms underpinning SLI.
    We applied exome sequencing technologies to five language-impaired individuals from this population and identified nine non-synonymous coding changes or splice site mutations that were present in at least three of the five affected individuals sequenced. Sequencing of the entire cohort identified a single non-synonymous coding change that was significantly more frequent in cases than controls (genotype frequencies of 46% and 11% respectively, p=4.48 × 10-5). We suggest that this rare coding variant may contribute to the elevated frequency of SLI in this population.

    Poster Presentation [ pdf]

    European Society of Human Genetics 2012

    Title: P09.126 - Investigating copy number variants within a cohort of individuals with specific language impairment
    Keywords: specific language impairment; copy number variation; developmental disorder
    Authors: Nuala H. Simpson1, Fabiola Ceroni1, Clyde Francks2, Samantha J. L. Knight1, Anthony P. Monaco1, Simon Fisher2, Dianne Newbury1, S L. I. Consortium1.
    1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 2Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands.
    Abstract: Specific language impairment (SLI) is a developmental language disorder that, in the absence of any comorbid neurological deficits, affects an individual’s spoken and/or receptive language despite adequate intelligence and accessibility to learning. SLI is a common childhood disorder with an estimated prevalence in pre-school children of up to 7%. It is a complex genetic disorder that is closely related to autism, dyslexia and ADHD. SLI has a high genetic component with twin studies finding a monozygotic concordance rate of up to 70%. Recent studies of neurodevelopmental disorders have implicated copy number variants (CNVs) in conditions such as autism, intellectual disability and ADHD. Therefore a study of CNVs within families containing individuals with SLI is currently being performed. The SLI consortium has collected a cohort of samples from across the UK that have been phenotypically well characterised for language. 176 of these families containing 186 individuals with SLI have been genotyped using the Illumina HumanOmniExpress beadchip that contains more than 700,000 SNPs. The SNP data is being used to identify CNVs across the genome using the copy number detection algorithms QuantiSNP and PennCNV. Data will be presented, for example, of the relative burden of CNVs in cases compared to their unaffected siblings and of novel variants. CNVs of interest are to be validated using quantitative PCR. To our knowledge this will be the first genome-wide CNV analysis performed within a cohort of samples with SLI.

    Poster presentation [ pdf


    You can follow me on twitter - @DianneNewbury

    Podcasts from our lab

    A podcast of my time on the Robinson Crusoe Island 

    A podcast (mp4) discussing the research of the Newbury lab.

    A scientific webcast (mp4) describing our research.

    An interview (mp3) with the Naked Scientists.

    An evening lecture at Science Oxford.

    If you enjoyed those, you might like these related podcasts:

    A podcast by Dorothy Bishop - ' Languages disorders in children: What can they tell us about genes and brains?'

    A podcast by Silvia Parachinni - ' Dyslexia and Genetics'

    A podcast by Peter Donnelly - ' The genetics of common human disease'.

    The RALLIcampaign youtube channel has several videos about language impairment.

    Dorothy Bishop has a blog on all things academic.