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.

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.

Publications

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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 Membership of a guidance 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 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