Developmental language impairments are neurodevelopmental disorders in which the acquisition of language, a task which children typically perform with ease, is hindered or fraught with difficulty. This work focuses on specific language impairment (SLI), a common and highly heritable language impairment in which language development is abnormal while other developmental domains are normal. Additionally, a case-study of a child with a broader linguistic and behavioural phenotype is also presented. The work described in this thesis includes both genetic and functional investigations which were aimed at identifying candidate genes for language impairment and provide insight into the genetic mechanisms that underlie language development. I performed a genome-wide association study of SLI which included child genotype effects, maternal genotype effects, parent-of-origin effects, and maternal-foetal interaction effects. This study found significant paternal parent-of-origin effects with the gene NOP9 on chromosome 14, and suggestive maternal parent-of-origin effects with a region on chromosome 5 which had previously been implicated in autism and ADHD. Case-control and quantitative association analyses of HLA genes and SLI identified several risk alleles and protective alleles. A case-control association analysis for related individuals which used an isolated population affected by SLI identified a non-synonymous coding variant in the gene NFXL1 which was significantly more frequent in affected individuals than in unaffected individuals. High-throughput sequencing of the coding regions of NFXL1 and LD blocks surrounding associated variants in ATP2C2, CMIP and CNTNAP2 (as reported in previous studies) identified novel or rare non-synonymous coding variants in NFXL1 and ATP2C2 in SLI families as well as intronic variants in all four genes that were significantly more frequent in SLI probands than in population controls. I describe a functional study of NFXL1 examining its expression in various brain regions, the presence of different splice variants across several tissues, its effect on genes it potentially interacts with, and the subcellular localisation of the protein. Finally, I present the case-study of a child with language impairment who had chromosomal rearrangements which spanned the location of FOXP2. I examine the potential influence the chromosomal rearrangements had on FOXP2 expression and describe a lincRNA gene which was disrupted by the chromosomal inversion. In conclusion, this work identified new candidate genes for language impairment, provided further support for the involvement of previously-identified candidate genes in SLI and contributed to the understanding of the molecular function of a newly-identified candidate gene for SLI.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:640099 |
| Date | January 2015 |
| Creators | Nudel, Ron |
| Contributors | Monaco, Anthony P.; Newbury, Dianne F. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:70249129-ef2e-4508-b8f6-50d6eae8e78b |
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