Gene selection for the Australian Reproductive Genetic Carrier Screening Project (“Mackenzie’s Mission”)

Abstract

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be lifelimiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for genephenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement.

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

“…The higher the score the more likely the gene is involved in a dominant disease, and the lower the pLI score, the more likely it is to indicate a recessive disease gene. To determine the appropriate pLI threshold for determining which AD-AR genes are more likely to be AR genes, we generated a reference list of pLI scores for manually curated 930 ARonly genes causing severe phenotypes 7,31 . The 95th percentile score for these genes was 0.86.…”

The ethics of preconception expanded carrier screening in patients seeking assisted reproduction

“…While NBS primarily aims at early detection and timely treatment of affected new-borns, in order to improve their prognosis, ECS serves informed reproductive decision making of prospective parents. For those NBS conditions (inborn errors of metabolism) where affected infants may die before the NBS result is communicated, or where part of the health damage involved cannot be avoided after NBS, it could be proportionate to also add the condition to the ECS panel ( Kirk et al , 2020 ). These programmes should, then, be conceived of as complementary ( Wilfond, 2009 ).…”

Ethical issues in reproductive genetic carrier screening

“…A significant component of designing a publicly funded RCS program is determining which genes warrant inclusion for testing. 10 Since screening can be stigmatising for people living with the genetic conditions screened for, it is considered most ethically defensible to screen only for genes associated with severe childhood-onset conditions. 1,3 However, because perceptions surrounding seriousness and severity are not purely objective, 9 any RCS program must carefully weigh the diverse ways in which a condition can present, as well as the implications of that condition for the person and their family.…”

“…Mackenzie's Mission is one of several large scale population-based RCS initiatives globally that have curated large panels of genes to test using a couplebased model. 5, 10,13 It is important for participants to understand that RCS is designed to provide the couple with information that might help with decisions about reproduction, rather than to convey genetic risk information for their own health. Participants will also be encouraged and supported to reflect on their values and their goals for testing, to help them decide whether this screening will be useful or important for them.…”