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

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 Univeristy, Birmingham, United Kingdom, 8University of Manchester, Manchester, United Kingdom, 9Univeristy 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 ZNF277 deletions 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 ZNF277 microdeletions 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 [pdf]

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]