Vestito, Letizia; (2023) Identifying deafness related genes from within the 100,000 Genomes Project. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Hearing loss (HL) is one of the most common sensory impairments in humans. It has a prevalence of around 1/500 in new-borns and is extremely heterogeneous, with an estimated 80% of prelingual HL cases having a genetic cause. Nevertheless, the diagnostic yield remains only between 20-30% depending on methods used. This PhD thesis, therefore, investigates novel analyses designed to improve the diagnosis of HL in patients recruited to the 100,000 Genomes Project (100KGP) and enable novel gene discovery. The first step was to identify and carefully define HL cohorts within the 100KGP. Studies were then performed to identify likely causal variants, using a variety of novel genomic approaches. Family-based analyses in previously undiagnosed patients were performed using enhanced bioinformatic pipelines lead to the identification of likely causal variants in BCAP31, MAGEL2 and PUS7, together with CNVs encompassing multiple genes. Development of a CRISPR-edited mouse Bcap31 mutant was used to validate the human missense mutation. In addition, several cohort-based analyses were performed, including the use of a gene burden test on the 100KGP HL cohorts. This gene agnostic approach was designed to detect the enrichment of rare, predicted pathogenic, segregating variants in cases compared to controls. This led to the identification of 18 known and 22 novel genes with significant disease-gene associations including ADAMTS4, AIM2, LAMC1, RSPO3 and TBX2. Next, a cohort-wide gene driven approach was investigated, performing a cross-cohort and cross-species comparison for associated genetic loci, first in mice with HL phenotypes identified by the International Mouse Phenotyping Consortium. Then, using similar methods, candidate loci from a GWAS study on UK Biobank data for self-reported adult hearing difficulty identified genes including NEDD4L, NISCH, KLHDC7B and CTBP2. Collectively, the results presented in this thesis provide important new insights for patients with HL, their clinical management and future research in this field.

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