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ASHG: Australian Newborn WES Project Combines Hearing Loss Dx With Optional Secondary Results

SAN DIEGO (GenomeWeb) – Researchers in Australia have explored the clinical implementation of genomics by offering whole-exome sequencing as a diagnostic test to families with newborns affected by hearing loss while at the same time allowing parents to obtain secondary findings that could affect their child's health in the future.

According to David Armor, a researcher at the Murdoch Children's Research Institute in Melbourne and at the University of Melbourne who presented the results here at the American Society of Human Genetics annual meeting, the project was one of several by the Melbourne Genomics Health Alliance to help guide the introduction of genomics into the healthcare system.

For the two-year cohort prospective study, he and his colleagues offered whole-exome sequencing to all families in Victoria, a state in southeastern Australia with a population of about 6.3 million, who had a child born with moderate or severe bilateral hearing loss in 2016 or 2017, as identified by the Victorian Infant Hearing Screening Program. 

Besides diagnostic results relating to the child's hearing loss, parents were also given the option to obtain screening results for either a list of 145 genes involved in childhood-onset conditions that have a known treatment or intervention or for a list of 222 genes that also included childhood-onset conditions that do not have a treatment. The gene lists were designed in collaboration with two US studies, Armor said, the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project and the BabySeq project.

Of 169 eligible families, they were able to contact 153 and ultimately consented 106 families for newborn exome sequencing and microarray analysis. For the diagnosis of hearing loss, the researchers focused on a panel of 143 genes known to be involved in deafness, though they have also been studying a broader panel of genes in a research context, Amor said. 

The overall diagnostic rate was about 60 percent. Specifically, 21 percent of patients had a mutation in the connexin 26 gene, 19 percent in other non-syndromic hearing loss genes, and 20 percent in genes related to syndromic deafness. In addition, 2 percent of patients had a confirmed infection with cytomegalovirus, which also causes hearing loss.  

Many of the remaining undiagnosed patients actually appear to have a variant in their exome that could explain their deafness, Amor said, but at the moment, those variants don't fulfill the criteria for being diagnostic. Since they are categorized as variants of unknown significance, further research will be needed to confirm that they are disease-causing.

Having a molecular diagnosis, he said, was beneficial to both families whose children have non-syndromic hearing loss, because they can use the information for future family planning, and to those with syndromic hearing loss, who gained prognostic information about their child's condition, allowing them to obtain regular screening for other problems that may develop in the future.

With regard to secondary results, 41 percent of families opted to receive information about the larger list of conditions that included untreatable ones, and 27 percent agreed to obtain results from the smaller list that only included conditions with a treatment or intervention. The remaining 32 percent decided that they only wanted the diagnostic results related to their child's hearing loss. 

Because both gene lists for this newborn screening part of the project were fairly constrained, Amor said, the researchers did not expect to have many hits and have so far only returned a single result.