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NEW SOUTH WALES, AUSTRALIAN CAPITAL TERRITORY

Lilian Downie, Jane Halliday, Sharon Lewis, David Amor Murdoch Children’s Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia; Royal Children’s Hospital, Melbourne, Victoria, Australia Background: Congenital hearing loss is now routinely detected and managed early through universal newborn hearing screening (1), the underlying genetic diagnosis is not. Access to genetic testing is usually limited due to lack of funding. New genomic testing techniques for congenital hearing loss have potential to streamline genetic diagnoses and thus tailor care. Aims: The aim of this study, offering universal exome sequencing to a population-derived cohort of newborn infants with moderate-profound bilateral hearing loss, was to determine the genetic aetiology. Our secondary aim was to describe the impact early genetic diagnosis had on care of these infants and evaluate cost-effectiveness. Methods: We recruited newborns born in the 2016-2017 calendar years in the state of Victoria, for whom hearing loss was detected through newborn hearing screening (2). All parents were offered clinical exome sequencing and chromosome microarray to investigate the cause of their infant’s hearing impairment (3). This pathway was costed and compared to the standard of care (GJB2/6 sequencing only) to calculate an incremental cost effectiveness ratio (ICER) determining cost-effectiveness for funders. Results: Of those approached, 68% (106/156) consented to participate. 56% (59/106) received a genetic diagnosis, compared to just 21% (22/106) for the previous standard of care. 38 infants were confirmed to have non-syndromic hearing impairment and 21 had early identification of a syndrome. Many of the 106 participants obtained important clinical benefits: 36% required no further surveillance for medical comorbidities related to hearing loss with other causes, 9% had tailored surveillance initiated, 2% were offered condition-specific treatment, and 4% had informed care for a complex neurodevelopmental syndrome (4). Recurrence risk was provided for all families whose child received a diagnosis. The ICER was $3333 per additional diagnosis representing cost-effectiveness (5). Conclusion: Exome sequencing was transformative in achieving a wide range of definitive diagnoses for the majority of infants. The high diagnostic yield and ability to provide tailored care, results in genomic sequencing being a cost-effective strategy that should become standard of care in the investigation of infants diagnosed with hearing impairment through newborn screening. References: 1. Wake M, Ching TY, Wirth K, Poulakis Z, Mensah FK, Gold L, et al. Population Outcomes of Three Approaches to Detection of Congenital Hearing Loss. Pediatrics. 2016;137(1). 2. Victorian Infant Hearing Screening Program. Available at http://infanthearing.vihsp.org.au/screening-and-diagnosis/ hearing-loss-in-children2017 (Accessed 7 February 2020). 3. Downie L, Halliday JL, Burt RA, Lunke S, Lynch E, Martyn M, et al. A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort. BMJ Paediatr Open. 2017;1(1):e000119. 4. Downie L, Halliday J, Burt R, Lunke S, Lynch E, Martyn M, et al. Exome sequencing in infants with congenital hearing impairment: a population-based cohort study. European Journal of Human Genetics: EJHG. 2019. 5. Downie L, Amor DJ, Halliday J, Lewis S, Martyn M, Goranitis I. Exome sequencing for isolated congenital hearing loss: a cost-effectiveness analysis. Laryngoscope. 2020. https://doi.org/ 10.1002/lary.29356.