Investigation of the genetic causes of Specific Language Impairment (SLI) in an isolated Chilean population
Lead Research Organisation:
UNIVERSITY OF OXFORD
Department Name: Wellcome Trust Centre for Human Genetics
Abstract
Many children have problems learning to use or understand language and this can for lots of different reasons. We study a particular type of language disorder known as Specific Language Impairment (or SLI). SLI is diagnosed in children who have normal intelligence and otherwise typical development but, for no apparent reason, have severe and persistent problems with language development. We know that SLI runs in families and is a complex genetic disorder. This means that some people carry certain gene combinations that, when accompanied by particular environmental factors, make them sensitive to language deficits. We are working with a population from an isolated island in Chile to try to identify genetic variations that predispose individuals to SLI. We are particularly interested in this island as they have an exceptionally high rate of language impairment (35%). We have already looked at their DNA and have identified five chromosome regions that are more similar in affected individuals than we would expect by chance alone. However, each of these regions is large and contains hundreds of genes. We are asking for a grant to study these chromosome segments in better detail and to investigate the role of possible alternative genetic mechanisms in this population. We hope that this research will allow us to identify specific genes and genetic elements that contribute to SLI susceptibility and help us to discover which protein networks are important in language acquisition processes.
Technical Summary
Specific Language Impairment (SLI) is diagnosed in children who experience profound and persistent language deficits despite otherwise normal development and no obvious explanatory factors. This disorder affects 5-8% of preschool children and has a complex genetic aetiology. Nonetheless, it is relatively under-studied and, to date, only three possible contributory loci have been identified.
Over the last two years, we have been working with researchers from the University of Chile to investigate an isolated population in whom 35% of the children meet criteria for SLI. We have completed genome-wide linkage analyses in this population and identified significant linkage to chromosomes 6, 7, 12, 13 and 17 (maximum NPL score=7.56, P=3.2x10-14).
In this application, we propose to extend these analyses by completing a comprehensive screen for common variations and rare mutations that may contribute to the high rate of SLI in this population. We will perform focussed association analyses of the identified linkage loci alongside genome-wide copy number variation and loss of heterozygosity investigations. Concurrent exome-sequencing of probands will enable the identification of rare coding mutations. All putative contributory variants (rare and common) will subsequently be investigated in British language-impaired families (SLI Consortium). This investigation has the power to identify numerous specific genetic variants that contribute to SLI susceptibility which will allow the formation of functional hypotheses.
Over the last two years, we have been working with researchers from the University of Chile to investigate an isolated population in whom 35% of the children meet criteria for SLI. We have completed genome-wide linkage analyses in this population and identified significant linkage to chromosomes 6, 7, 12, 13 and 17 (maximum NPL score=7.56, P=3.2x10-14).
In this application, we propose to extend these analyses by completing a comprehensive screen for common variations and rare mutations that may contribute to the high rate of SLI in this population. We will perform focussed association analyses of the identified linkage loci alongside genome-wide copy number variation and loss of heterozygosity investigations. Concurrent exome-sequencing of probands will enable the identification of rare coding mutations. All putative contributory variants (rare and common) will subsequently be investigated in British language-impaired families (SLI Consortium). This investigation has the power to identify numerous specific genetic variants that contribute to SLI susceptibility which will allow the formation of functional hypotheses.
Planned Impact
UNICEF, UNESCO and the World Health Organization include communication in their core life skills and, in the UK, communication, language and literacy form one of the six target areas of Early Years education. Deficits in communication can disrupt social, emotional and educational development and increase the risk of behavioural disorders, unemployment and mental health issues. Yet, research in this area is relatively under-represented (Bishop 2011). The Bercow report, commissioned by the government in 2007, stressed the importance of raising awareness of communication disorders. The research topic of our project is thus an area of agreed importance. The identification of risk genetic variants will inform our understanding of the aetiological basis of speech and language impairments. The involvement of cohorts from different ethnic groups will provide data regarding the universality of identified risk factors and subsequent investigations in developmentally delayed individuals will develop our appreciation of cross-disorder effects. The primary direct beneficiaries of this research will be:
The inhabitants of the Robinson Crusoe Island - There is no speech and language professional resident on Robinson Crusoe Island. This is because the percentage of municipal funds allocated to the island for speech and language support are based on mainland frequencies of SLI, which predict that just one or two Islanders will be affected. Prof Villanueva's previous study (2008) clearly demonstrated an increased incidence of speech and language problems on the Island and established the need for a systematic review of the treatment of Island children. As a direct result of this, increased municipal funds have now been acquired to hire and retain a resident speech and language pathologist providing educational and social support for affected children in both oral and written language. This additional support will follow the system used on the mainland and will assist transition between the island and mainland. This will be of particular importance to those children wishing to continue into higher education, which must be completed on the mainland. Thus Prof Villanueva has developed a strong relationship with this community. Her advice and support is recognised and appreciated and her research has the proven ability to benefit the residents. She has developed standardised language tests which are used to accurately assess affected islanders and provides ongoing advice for resident teachers and the families of affected individuals.
Families of the SLI Consortium - To date, over 300 families have contributed to the SLI Consortium collection. All children in this sample, regardless of linguistic status, have contributed DNA samples and completed psychometric analyses. These families tell us that our research is important as it might help to explain some of the reasons why their child is affected. They have noticed that SLI runs in families and feel genetics plays a strong role in the aetiology of SLI.
The wider picture - At the very minimum, our research promotes awareness of communication disorders. A better awareness of the aetiology may be a key step in understanding and conceptualising these impairments and categorising relationships with other aspects of development. When combined with behavioural and complementary genetic research, our investigations may lead to translational research through the development of identification and intervention systems or the discovery of specific subgroups not recognised within the current spectrum. Thus, in the longer term, the achievement of our aims will impact, not only the families of individuals with SLI, but individuals with developmental disorders, clinicians, educational and social policy makers, and society as a whole.
The inhabitants of the Robinson Crusoe Island - There is no speech and language professional resident on Robinson Crusoe Island. This is because the percentage of municipal funds allocated to the island for speech and language support are based on mainland frequencies of SLI, which predict that just one or two Islanders will be affected. Prof Villanueva's previous study (2008) clearly demonstrated an increased incidence of speech and language problems on the Island and established the need for a systematic review of the treatment of Island children. As a direct result of this, increased municipal funds have now been acquired to hire and retain a resident speech and language pathologist providing educational and social support for affected children in both oral and written language. This additional support will follow the system used on the mainland and will assist transition between the island and mainland. This will be of particular importance to those children wishing to continue into higher education, which must be completed on the mainland. Thus Prof Villanueva has developed a strong relationship with this community. Her advice and support is recognised and appreciated and her research has the proven ability to benefit the residents. She has developed standardised language tests which are used to accurately assess affected islanders and provides ongoing advice for resident teachers and the families of affected individuals.
Families of the SLI Consortium - To date, over 300 families have contributed to the SLI Consortium collection. All children in this sample, regardless of linguistic status, have contributed DNA samples and completed psychometric analyses. These families tell us that our research is important as it might help to explain some of the reasons why their child is affected. They have noticed that SLI runs in families and feel genetics plays a strong role in the aetiology of SLI.
The wider picture - At the very minimum, our research promotes awareness of communication disorders. A better awareness of the aetiology may be a key step in understanding and conceptualising these impairments and categorising relationships with other aspects of development. When combined with behavioural and complementary genetic research, our investigations may lead to translational research through the development of identification and intervention systems or the discovery of specific subgroups not recognised within the current spectrum. Thus, in the longer term, the achievement of our aims will impact, not only the families of individuals with SLI, but individuals with developmental disorders, clinicians, educational and social policy makers, and society as a whole.
Publications

Ceroni F
(2015)
Reply to Pembrey et al: 'ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis'.
in European journal of human genetics : EJHG

Ceroni F
(2014)
Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.
in European journal of human genetics : EJHG

Chen XS
(2017)
Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.
in Scientific reports

De Barbieri Z
(2018)
Family aggregation of language impairment in an isolated Chilean population from Robinson Crusoe Island.
in International journal of language & communication disorders

Devanna P
(2018)
Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders.
in Molecular psychiatry


Dianne Newbury
(2012)
Current Issues in developmental disorders

Hidecker M
(2014)
Speaking the same language: genetics and communication disorders
in Developmental Medicine & Child Neurology

Howey R
(2015)
Increased Power for Detection of Parent-of-Origin Effects via the Use of Haplotype Estimation.
in American journal of human genetics

Moralli D
(2015)
Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2
in Molecular Cytogenetics
Title | cell, cell, cell |
Description | I was involved in the production of a film that was shown at planetariums around the country. The film is the story of the trillions of cells that form our bodies, from our beginnings as a single cell to the complexity of a whole body: it's the story of who we are. |
Type Of Art | Film/Video/Animation |
Year Produced | 2012 |
Impact | The film was initially shown at intech science centre in Winchester and has since been shown at several planetariums around the country. |
URL | http://cell-cell-cell.com/ |
Description | college of reviewers for the Newton Fund |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | http://www.mrc.ac.uk/research/international/the-newton-fund/ |
Description | Newton |
Amount | £348,000 (GBP) |
Funding ID | ES/N01913X/1 |
Organisation | Economic and Social Research Council |
Sector | Public |
Country | United Kingdom |
Start | 02/2016 |
End | 09/2018 |
Description | Centre for Reading and Language |
Organisation | University of York |
Department | Centre for Reading and Language (CRL) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have applied for and won a Newton grant to work with psychologists from the Centre for Reading and Language to develop a reading intervention programme in Chile |
Collaborator Contribution | Our partners will help us to develop the programme |
Impact | Newton award |
Start Year | 2015 |
Description | Nijmegen |
Organisation | Max Planck Society |
Department | Max Planck Society Language and Genetics Department |
Country | Germany |
Sector | Academic/University |
PI Contribution | We have been collaborating with the Max Planck institute to perform exome sequencing studies of individuals with SLI. |
Collaborator Contribution | Intellectual input and genomic facilities |
Impact | Data from this project was presented at the International Congress of Human Genetics in 2011 |
Description | UC Davis |
Organisation | University of California, Davis |
Department | School of Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | We are collaborating with UC Davis to perform whole genome sequencing in this cohort |
Collaborator Contribution | UC Davis will provide the sequencing |
Impact | The collaboration has only just been formed so no outputs are available yet |
Start Year | 2014 |
Description | University of Chile |
Organisation | University of Chile |
Country | Chile |
Sector | Academic/University |
PI Contribution | We have performed the genetic analyses in this collaboration |
Collaborator Contribution | Sample collection and intellectual input |
Impact | We collaborate with researchers from the Univeristy of Chile in the investigation of SLI in an isolated population. The researchers at the Univeristy have direct contact with the population and have collected DNA, genealogical data and linguistic measurements from the Islanders. We conducted genetic analyses of the population in collaboration with core statistical support at the Wellcome Trust Centre for Human Genetics. These data resulted in a publication in 2011 and were presented as a platform presentation at the International Congress of Human Genetics in 2011. This collaboration is ongoing and collaborative grant applications are under consideration. |
Start Year | 2009 |
Description | Castang |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | I was invited to give a talk at a recent workshop entitled 'Audition, Perception and Language Acquisition' funded by the Castang foundation. The meetings bring together a wide range of disciplines, including participants with direct clinical roles, to further understanding of the nature of problems that children can experience in listening effectively and acquiring language. The longer term aim is to improve assessment and intervention. The meeting was attended by 20 researchers from a wide range of disciplines |
Year(s) Of Engagement Activity | 2012 |
Description | Colloquium for the Study of Language |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | My student was invited to talk at the Colloquium for the Study of Language at Tel Aviv University, Israel Interaction with International scientists from multiple disciplines |
Year(s) Of Engagement Activity | 2011 |
Description | II Jornadas Internacionales TEL |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I presented at a day for families and practitioners affected by speech and language disorders. The day included talks from professionals and debates. The organisers said they had invited me because they had seen a podcast of my research on youtube. |
Year(s) Of Engagement Activity | 2016 |
URL | http://jornadastelonline.com/ |
Description | MRC International Poster competition |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | I presented a poster at the MRC International Poster competition. The presentation involved discussion with researchers, policymakers. The poster won first prize The competition prize was covered on our centre website and in the MRC Network magazine. We were asked to provide a blog for the MRC website on the project |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.insight.mrc.ac.uk/2013/12/11/celebrating-a-century-of-international-collaboration/ |
Description | MRC talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | I was invited to give a talk to MRC career development Fellows about my experience of being a Fellowship holder |
Year(s) Of Engagement Activity | 2015 |
Description | Manchester University presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | 20 individuals (students and researchers) attended a talk with discussion after Ongoing collaboration with University of Manchester |
Year(s) Of Engagement Activity | 2011,2014 |
Description | Oxford Language Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | I was invited to give a talk at the Oxford Language Symposium I met researchers and interested students at the University |
Year(s) Of Engagement Activity | 2012 |
Description | Oxford Sparks |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | Oxford Sparks is a new science resource from Oxford University. Covering physical, life and medical sciences and packed with videos, apps, games and activities, Oxford Sparks has plenty to interest students. I took part in a meet the scientists Q&A feature on the Oxford sparks website |
Year(s) Of Engagement Activity | 2012 |
Description | Papers in plain English |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | For each of our primary publications, we have pledged to release a "papers in plain English" sheet which describes the findings of the paper in general terms. These papers are available on our website. People have e-mailed to thank me for this and it has prompted Twitter and e-mail discussions |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.well.ox.ac.uk/newbury |
Description | Podcast |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I made a podcast about our trip to the Robinson Crusoe Island and our research there. The podcast can be found on our website |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.well.ox.ac.uk/assets/files/rcvideo1.mp4 |
Description | Podcast interview |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I gave an interview for the naked scientists which was published as an mp3 on their website I have been approached by the naked scientists for a feature article on our work |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.thenakedscientists.com/HTML/content/interviews/interview/1000141/ |
Description | SET for Britain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | I was a finalist in the SET for Britain compensation. We presented a poster at the Houses of Parliament in an event for politicians and policymakers The competition was featured on the centre website |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.setforbritain.org.uk/2014event.asp |
Description | STEM ambassador training |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | By volunteering as an Ambassador, you could be opening up life-changing opportunities for many young people in your area. Anyone who has a desire to inspire children and young people in STEM subjects can become an Ambassador. The main qualities that all Ambassadors share are enthusiasm and commitment, along with a passion for what they do. I have been asked to give a talk at a local school to their biomedical society |
Year(s) Of Engagement Activity | 2012 |
Description | Science Oxford evening lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I gave an invited talk at the science museum in Oxford. I have had lots of e-mails exchanges with people at the talk and gained many Twitter followers. A podcast of the talk is available online |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.ndm.ox.ac.uk/dianne-newbury-freeing-voices |
Description | Scientific presentation (Institute Psychiatry) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | 30 people attended a talk at the institute of psychiatry about our work I met potential collaborators and researchers in the field |
Year(s) Of Engagement Activity | 2012 |
Description | Talk at Yale |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | I gave a talk to undergraduate students and researchers at Yale with discussion after The talk led to a collaboration with researchers from Yale I was invited to visit the Haskins lab |
Year(s) Of Engagement Activity | 2014 |
Description | Talking genetics with Robinson Crusoe - talk at UBC |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | A scientific talk to members of the Social Exposome group at University of British Colombia. The talk was on zoom and so was able to be attended by people from around the world including students and researchers from outside of my immeaditae discipline. 150 people attended the talk |
Year(s) Of Engagement Activity | 2021 |
Description | lecturing and tutorials |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | I have given lectures and tutorials in the neurosciences, immunology, medical sciences, biomedical seciences, physiology and linguistics departments this year. Average attendance at lectures is 10-20 students. Tutorials are 1-2 students I have received an increasing number of requests to give tutorials and lectures in the University. We have had new course content covering genetics accepted by the linguistics department. I have secured a tutorial position at Somerville College (Oxford University) |
Year(s) Of Engagement Activity | 2010,2011,2012,2013 |
Description | podcast |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The podcsat is available from the department website and forms one of a growing number of available podcsats regarding research in our department I have had e-mails from parents of affected children saying they have seen the podcast |
Year(s) Of Engagement Activity | 2011 |
Description | school visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 8 pupils from a local school spent a day in the lab. This sparked discussions regarding careers in science |
Year(s) Of Engagement Activity | 2015 |
Description | school workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | My postdoc facilitated an outreach activity for sixth formers where they extracted their DNA and put it in a necklace engagement of local schools |
Year(s) Of Engagement Activity | 2012 |
Description | work experience |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | We house 5-10 work experience students for a week in our lab All students were asked to write blog-type posts for our website. The student group for 2014 mentioned that they had been inspired by previous student blogs. One student from 2013 e-mailed me to let me know that she had been awarded a place to study biomedical science at Oxford after being inspired by the work experience. |
Year(s) Of Engagement Activity | 2013,2014,2015 |
URL | http://www.well.ox.ac.uk/blog-of-work-experience-students |