Crystle Lee¹, Sebastian Hollizeck¹, Paul de Fazio¹, Ain Roesley¹, Belinda Chong¹, Simon Sadedin^1,2, Sebastian Lunke^1,2,3

¹ Victorian Clinical Genetics Services, Melbourne, Victoria

² Murdoch Children’s Research Institute, Melbourne, Victoria

³ University of Melbourne, Melbourne, Victoria

Background: Expanded carrier screening (ECS) aims to identify couples at risk of having children with a severe, early-onset recessive condition. The benefits of ECS have been widely reported, driving the uptake of this test. Performing ECS at scale presents a major challenge for diagnostic laboratories. Consequently, improving efficiencies through automated workflows is crucial.

Aim: We developed a workflow that minimises manual interaction to enable large-scale, high-throughput, couple-based expanded carrier screening. 

Method: The Illumina Emedgene platform, combined with custom in-silico proband variant calling, was used to develop a prioritisation strategy which uses annotations from various databases to identify candidate variants of interest. Couples with no variants of interest are automatically progressed to a low-chance report. To validate the algorithm, we used 34 known “high chance” and 40 known “low chance” couples. 

Results: All known “high chance” couples were correctly identified, and 55% of known “low chance” couples were progressed to automatic reporting. The remaining 45% returned variants for manual curation, none of which were reportable.

Conclusion: Workflows utilizing automated processes and optimised variant calling strategies facilitate the delivery of ECS at scale. Various improvements have been identified which will further improve the workflow.