A population study of exome sequencing in congenital hearing impairment

Dr Lilian Downie1,2,3,4, MBBS. Professor Jane Halliday2,4, Rachel Burt2,4, PhD. Sebastian Lunke1,2,4, PhD. Ms Elly Lynch1,2,5, Grad Dip Genetic Counselling. Melissa Martyn2,5, PhD. Zeffie Poulakis2,3,4, D Psych. Clara Gaff 4,5, PhD. Valerie Sung2,3,4, PhD. Melissa Wake2,4, MBChB MD. Matthew F Hunter6,7, MBChB FRACP. Kerryn Saunders6,7, MBBS FRACP. Elizabeth Rose2,3,4 MBBS FRACS. Sharon Lewis2,4, PhD. Anna Jarmolowicz1,2,5, Grad Dip Genetic Counselling. Dean Phelan1,2Heidi L Rehm8, PhD. Professor David J Amor1,2,3,4, PhD.

 1Victorian Clinical Genetics Services, Melbourne Australia.

 2Murdoch Children’s Research Institute, Melbourne Australia

3Royal Children’s Hospital, Melbourne Australia.

4University of Melbourne, Melbourne Australia

5Melbourne Genomics Health Alliance, Melbourne Australia.

6Monash Health, Melbourne Australia.

7Monash University, Melbourne Australia.

8Massachusetts General Hospital and the Broad Institute or MIT and Harvard, Boston MA USA.


Background: The Melbourne Genomics Health Alliance is establishing systems and producing evidence to guide incorporation of genomics into the Victorian healthcare system. Through one of its clinical flagship projects, the Alliance offered exome sequencing to all Victorian families who had an infant with moderate, severe or profound bilateral hearing impairment born in 2016 or 2017.

Aim: The aim of this project was to define the genetic aetiology of congenital hearing impairment in a population-based cohort.

Methods:  Families who had an eligible child were identified by the Victorian Infant Hearing Screening Program (VIHSP). Exome sequencing with targeted gene analysis was performed in conjunction with microarray.

Results: 106 participants were recruited. 61 have received a genetic diagnosis, providing a rate of diagnosis of 58%. 21% have connexin mutations, 17% have another non-syndromic deafness gene identified, 19% have a syndromic diagnosis. Microarray has contributed to 11% of diagnoses when combined with exome sequencing results.  Having a molecular diagnosis has resulted in a change in management for 48% of participants, this has included stopping or initiating screening, prophylactic treatment or re-direction of care.

Discussion: Adding exome sequencing and microarray to the investigation pathway for this cohort has led to a genetic diagnosis in approximately two thirds of infants with congenital hearing impairment. The genetic diagnoses related to hearing impairment are broad and can have implications in the management of children.

Conclusion: This study provides a comprehensive understanding of the genetic aetiology of congenital hearing loss in our population over this two year period.


Lil graduated from medical school at Monash University in 2009 and undertook paediatric training at the Royal Children’s Hospital in Melbourne in 2011. Lil is currently a Clinical Genetics Fellow at the Victorian Clinical Genetics Service. She is also completing her PhD through the University of Melbourne and Murdoch Children’s Research Institute on the genetics of deafness and genomic newborn screening. This project is funded by the Melbourne Genomics Health Alliance in partnership with the Victorian State Government. The Alliance is a group of 10 healthcare and research organisations establishing systems to integrate genomics into healthcare in Victoria.