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A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort
  1. Lilian Downie1,2,3,4,
  2. Jane L Halliday2,4,
  3. Rachel A Burt2,4,
  4. Sebastian Lunke1,2,4,
  5. Elly Lynch5,6,
  6. Melissa Martyn2,5,
  7. Zeffie Poulakis2,3,4,
  8. Clara Gaff4,5,
  9. Valerie Sung2,3,4,
  10. Melissa Wake2,4,7,
  11. Matthew Hunter8,9,
  12. Kerryn Saunders8,9,
  13. Elizabeth Rose2,3,4,
  14. Heidi L Rehm10,
  15. David J Amor1,2,3,4
  1. 1 Victorian Clinical Genetics Services, Victoria, Melbourne, Australia
  2. 2 Murdoch Children’s Research Institute, Victoria, Melbourne, Australia
  3. 3 Royal Children’s Hospital, Victoria, Melbourne, Australia
  4. 4 Department of Paediatrics, University of Melbourne, Victoria, Melbourne, Australia
  5. 5 Melbourne Genomics Health Alliance, Victoria, Melbourne, Australia
  6. 6 Austin Health, Victoria, Melbourne, Australia
  7. 7 University of Auckland, Auckland, New Zealand
  8. 8 Monash Health, Victoria, Melbourne, Australia
  9. 9 Monash University, Victoria, Melbourne, Australia
  10. 10 Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Professor David J Amor; david.amor{at}


Introduction The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant’s hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss. Parents will also be offered the opportunity to receive additional results from their infant’s WES.

Methods Eligible infants will be identified through the Victorian Infant Hearing Screening Program and offered an appointment in a paediatrician-run clinic, a genetics assessment and enrolment in the Victorian Childhood Hearing Impairment Longitudinal Databank. If parents consent to WES, genes causing deafness will be analysed and they can choose to obtain additional findings. For the additional results component, a modified laboratory protocol has been designed for reporting of results in the absence of a relevant phenotype. Parents’ experience of being offered WES will be evaluated using surveys.

Discussion This project will provide descriptive analysis of the genetic aetiology of congenital hearing loss in this cohort and may provide data on genotype–phenotype correlations. Additionally, choices regarding additional findings will be analysed. Participants will represent a diverse cross section of the population, increasing the ability to generalise results beyond the study group. Evaluation surveys will allow analysis of preferences around counselling, usefulness of a decision aid and adequacy of information provision.

  • Deafness
  • Genetics
  • Screening

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  • Contributors LD drafted the manuscript, DA, RB, JH, CG and EL were major contributors to the design of the study protocol, SL established the laboratory protocol, and MM designed the evaluation surveys. ZP, MW, KS, MH, VS and ER have made substantial contributions to recruitment design. HLR, JH and CG were collaborators in designing gene lists. All authors read and approved the final manuscript.

  • Funding The study was funded by the founding organisations of the Melbourne Genomics Health Alliance (Royal Melbourne Hospital, Royal Children’s Hospital, University of Melbourne, Walter and Eliza Hall Institute, Murdoch Children’s Research Institute, Australian Genome Research Facility (AGRF) and CSIRO) and the State Government of Victoria (Department of Health and Human Services). The involvement of AGRF was supported by sponsorship from Bioplatforms Australia and the NCRIS program.

  • Competing interests None declared.

  • Ethics approval The establishment of this project was approved by the Royal Melbourne Hospital Human Research Ethics Committee as an amendment to the Melbourne Genomics protocol 2013.245.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

  • Collaborators Collaborators in the Melbourne Genomics Health Alliance include Libby Smith, Bibi Gerner, Nessie Mupfeki, Michelle Burns, Ivan Macciocca, Gemma Brett,Anna Jarmolowicz, Yael Prawer, Belinda Chong, Jonathan Berg, Cynthia Powell, Holly Feller and Emily Shepard.

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