Unravelling the genetic relationships between auditory processing and speech and language

Auditory processing disorder is a common developmental disorder affecting about 10% of children. It is characterised by poor perception of speech sounds, especially in background noise environments, despite normal hearing sensitivity, which can lead to poor performance in school with a negative impact on education and everyday life. Previous studies have shown that auditory processing skills have a substantial genetic component, however, it is not clear which genes or molecular mechanisms are involved. In this thesis three different genetic approaches are applied (monogenic, common disease-common variant and common disease-rare variant) to assess the effect of candidate genes on neurodevelopmental measures, including hearing and language phenotypes, in a population cohort (ALSPAC) of more than 14,000 children. To complement these analyses, a reverse phenotype to genotype approach is used, focussing on a surrogate measure of auditory processing difficulties in ALSPAC children, to identify potential high impact coding variants that may explain these difficulties. Given previous work, these genetic investigations focus upon candidate genes related to Usher syndrome, a recessive disorder leading to hearing and vision loss resulting from dysfunctional neurosensory cells in the inner ear and retina (hair cells and photoreceptor cells respectively). Analyses indicate that there is no one single risk variant, but a complex mix of variation across Usher genes (such as USH2A, PCDH15, CLRN1, and ADGRV1) might explain some of the APD risk. The phenotype to genotype analysis across coding regions further shows that rare pathogenic variants with large effect in other genes (such as GRHL3, DIAPH1, FAT4 and IFT88) can contribute to risk of APD in simplex cases. These results provide insights into the genetic landscape underlying APD and offer candidate genes and variants for further investigation and validation. Furthermore, the results highlight allelic heterogeneity where multiple variants present in the same Usher gene (USH2A) can display different, but related hearing phenotypes. In a wider context, this study also highlights the viability of using related/surrogate phenotypes for genetic discovery in a large sample when deep phenotyping of APD is unavailable