Laboratory Considerations for Reproductive Genetic Carrier Screening: Experiences from Mackenzie's Mission

The Australian Reproductive Genetic Carrier Screening Project, "Mackenzie's Mission," performed couple-based screening for 9107 reproductive couples for >1280 genes associated with severe autosomal and X-linked recessive disorders. It identified close to 1:50 participating couples as having a previously unknown increased risk of having children with a condition screened. Here, the processes, successes, and challenges of the laboratory testing undertaken during Mackenzie's Mission are described. Samples were mouth swabs, self-collected and posted to one of three testing laboratories. Two laboratories used exome sequencing; the other used a targeted gene panel. Both were equally effective in identifying increased risk couples for small sequence variants. FMR1 and SMN1 testing were performed separately. A Variant Review Committee met weekly to discuss reportable variants and variants difficult to classify. This promoted consistent reporting. Exclusion of variants previously classified by a laboratory as benign, likely benign, and/or variant of uncertain significance significantly reduced the analysis required for each reproductive couple. The pan-ancestral screening approach was suitable for data from people of various ancestries despite the increased analysis time required for data from couples of African, Middle Eastern, and Asian ancestry. For consanguineous couples, there was a significant increase in the number of variants requiring review and approximately 10-fold more increased risk reports issued. This study demonstrated large-scale, pan-ancestral reproductive genetic carrier screening is feasible across Australia's diverse population.