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PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

Hearing loss is the most common sensory disorder in children. Over 50% of these cases are genetic, and more than 100 genes have been associated with inheritance and different patterns of hearing loss. Identifying the underlying aetiology of hearing loss is paramount in the diagnosis and management of hearing loss, but the vast clinical and genetic heterogeneity poses a diagnostic challenge. This is problematic because if left untreated, hearing loss can have negative impact on quality of life, language, and social development. Genomic sequencing strategies have demonstrated clinical utility in many genetic conditions with similar diagnostic challenges. In this thesis, approaches were taken to study the diagnostic performance of genomic strategies currently used in the clinic, understand how genomic strategies perform when used with patients with hearing loss, and how integrated genomic and clinical data can reveal insights to inform personalised patient care.Clinical exome sequencing (CES) analysis data and molecular results from 400 patients with rare disorders were analysed. CES results from a subset of 60 patients with ear abnormalities and hearing loss disorders were further studied. To obtain insights into the integrated use of clinical and genomic data, a phenotype-genotype correlation was conducted in patients with USH2A-related disease. Findings from this correlation were further validated using two external datasets. In addition, a review article highlights potential of genomic strategies in current management of patients with hearing loss and the potential benefit of obtaining a molecular diagnosis through genomic sequencing for cochlear implant candidates and recipients.CES in rare disease patients was reported with an overall 24% diagnostic rate. Nervous system, head and neck, skeletal, ear and eye abnormalities were the most commonly reported clinical features in the patient cohort referred for CES. The use of different methods of phenotype-driven gene selection approaches for virtual panels clearly demonstrated a reduction of variant workload without compromising diagnostic rate. Sixty patients with ear disorders and hearing impairment underwent CES. Here, CES was reported with a diagnostic rate of 31%. CES results informed further diagnostic steps in 25% of patients with hearing impairment. The phenotype-genotype correlation in patients with USH2A-related disease identified the presence of specific alleles in patients with retinitis pigmentosa and unaffected hearing or late-onset, mild hearing loss. Furthermore, patients with congenital-onset and moderate-to-severe hearing loss were found to harbour protein truncating variants in their genotypes. Audiological surveillance could then be personalised based on the phenotype anticipated by the molecular diagnosis.In conclusion, this study has demonstrated that clinical genomic sequencing can be a comprehensive and powerful tool in the investigation of genetic congenital and childhood-onset hearing loss. Integrated genomic and clinical data can enable precision medicine approaches in children with genetic hearing loss. This work adds to the increasing body of evidence that supports the use of genetic diagnosis as a potential prognostic factor to inform patient care and hearing habilitation and rehabilitation strategies.

Hearing loss is the most common sensory disorder in children. Over 50% of these cases are genetic, and more than 100 genes have been associated with inheritance and different patterns of hearing loss. Identifying the underlying aetiology of hearing loss is paramount in the diagnosis and management of hearing loss, but the vast clinical and genetic heterogeneity poses a diagnostic challenge. This is problematic because if left untreated, hearing loss can have negative impact on quality of life, language, and social development. Genomic sequencing strategies have demonstrated clinical utility in many genetic conditions with similar diagnostic challenges. In this thesis, approaches were taken to study the diagnostic performance of genomic strategies currently used in the clinic, understand how genomic strategies perform when used with patients with hearing loss, and how integrated genomic and clinical data can reveal insights to inform personalised patient care.Clinical exome sequencing (CES) analysis data and molecular results from 400 patients with rare disorders were analysed. CES results from a subset of 60 patients with ear abnormalities and hearing loss disorders were further studied. To obtain insights into the integrated use of clinical and genomic data, a phenotype-genotype correlation was conducted in patients with USH2A-related disease. Findings from this correlation were further validated using two external datasets. In addition, a review article highlights potential of genomic strategies in current management of patients with hearing loss and the potential benefit of obtaining a molecular diagnosis through genomic sequencing for cochlear implant candidates and recipients.CES in rare disease patients was reported with an overall 24% diagnostic rate. Nervous system, head and neck, skeletal, ear and eye abnormalities were the most commonly reported clinical features in the patient cohort referred for CES. The use of different methods of phenotype-driven gene selection approaches for virtual panels clearly demonstrated a reduction of variant workload without compromising diagnostic rate. Sixty patients with ear disorders and hearing impairment underwent CES. Here, CES was reported with a diagnostic rate of 31%. CES results informed further diagnostic steps in 25% of patients with hearing impairment. The phenotype-genotype correlation in patients with USH2A-related disease identified the presence of specific alleles in patients with retinitis pigmentosa and unaffected hearing or late-onset, mild hearing loss. Furthermore, patients with congenital-onset and moderate-to-severe hearing loss were found to harbour protein truncating variants in their genotypes. Audiological surveillance could then be personalised based on the phenotype anticipated by the molecular diagnosis.In conclusion, this study has demonstrated that clinical genomic sequencing can be a comprehensive and powerful tool in the investigation of genetic congenital and childhood-onset hearing loss. Integrated genomic and clinical data can enable precision medicine approaches in children with genetic hearing loss. This work adds to the increasing body of evidence that supports the use of genetic diagnosis as a potential prognostic factor to inform patient care and hearing habilitation and rehabilitation strategies.