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 life-limiting 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 gene-phenotype 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.

Fig. 1. The Mackenzie’s Mission gene list selection process.

2397 genes were assessed in total, identified from two sources: the OMIM database and existing gene lists used for carrier screening. Review by clinical geneticists divided the genes into four categories: GREEN—Include; RED—Exclude; BLUE—Review evidence for gene-phenotype relationship; ORANGE—Consult gene selection committee. BLUE genes were reviewed for evidence of a gene-phenotype relationship. ORANGE genes were discussed by the gene selection committee. The result was a list of 1300 genes selected for use in Mackenzie’s Mission.