Investigation of the genetic causes of Specific Language Impairment (SLI) in an isolated Chilean population

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.

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.

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.