1435 Rapid exome sequencing in acutely unwell children – providing new diagnostic options in intensive care settings

Background Rapid exome and genome sequencing in acutely unwell children has become increasing available worldwide over the last five years. The diagnostic rate is variable; however most relevant literature highlights the importance of the effect of a genetic diagnosis on the management in acute neonatal (NICU) and paediatric intensive care (PICU) settings. NHS England published the National Genomic Test Directory to integrate and embed genomic testing into mainstream medicine. The test directory lists genetic testing for different disorders and ‘R14’ was allocated to the rapid exome sequencing service for acutely unwell babies and children with a potentially monogenic disorder. R14 service was launched by NHS England on 1st October 2019. The service is delivered by the Exeter Genomics Laboratory, South West Genomic Laboratory Hub, running in collaboration with clinical genetics units. The main aims are to provide rapid genetic diagnosis to influence acute management and provide equity of access. Objectives This study is a retrospective service evaluation and analysis of all cases recruited during the first year of the R14 service in England from 1st October 2019 until 30th September 2020. The primary and secondary outcomes focus on assessing turn-around-time (TAT), diagnostic rate and management impact of a rapid genetic diagnosis. Methods A standardised proforma was created and eligible patients were identified through the electronic database at the Exeter Genomic Laboratory. The proformas were pre-populated with the molecular findings, circulated to the 17 regional clinical genetics centres and completed using patient notes. Anonymised data were collated and analysed using Microsoft Excel. Results 361 acutely unwell children were included. 53%(192/361) were male. Patient age groups were neonates 40%(144), infants 40%(143), children 20%(72), two unknown. 50%(182) were recruited from NICU, 26%(93) PICU, 24%(86) ward or home. 91%(329/361) were trio samples. The median TAT was 11 days from receipt of the DNA samples in the Exeter laboratory to the final report. The majority(331/361, 92%) received a final report within the 21-day TAT standard. 14/30 were delayed to allow additional testing where preliminary results were re-classified to diagnoses. The diagnostic rate was 38%(141/361). The result influenced management in 94%(133/141) of these patients. Impact of diagnosis on management In 75%(100/133), the diagnosis directly influenced management for the proband or family members. In a further 25%(33/133), diagnosis was helpful solely for discussing precise recurrence risk and prenatal diagnosis offered if indicated. 32%(43/133) were referred to a specialist for the condition; 16%(23/133) informed re-orientation and palliative care. Current management and prognosis were supported in 16%(22/133) and specific treatment such as transplant or medication was provided in 13%(19/133). Specific screening was arranged in 5%(7/133). Conclusions This is the first NHS-based diagnostic service which provides rapid genetic diagnoses in acutely unwell children and the largest reported cohort of patients undergoing rapid exome sequencing. It demonstrates that this innovative and transformational national service has successfully provided rapid results while maintaining a high diagnostic rate. Most importantly, diagnoses have influenced both acute management in intensive care settings and long term management for children and their immediate and extended family members.