mackenzie's mission: the australian reproductive carrier screening project

Conditions: X-Linked Genetic Diseases; Autosomal Recessive Disorder

Summary: this study will investigate reproductive genetic carrier screening (rgcs) in 10,000 couples across australia. carrier screening for approximately 1300 genes associated with severe, childhood-onset, x-linked and autosomal recessive conditions will be performed on each member of the couple. a combined result will be issued indicating whether the couple has a 'low' or 'increased' risk of having a child with a genetic condition. it is anticipated that 1-2% of couples will be at an increased risk of having an affected child. the study will evaluate all aspects of the rgcs program to assess the feasibility and acceptability of a publicly-funded population-wide rgcs program, including: * education of recruiting healthcare providers * education of participating couples * implementation and uptake of rgcs * frequency of increased-risk couples and their reproductive decisions * psychosocial impacts * ethical issues * health economic implications * health implementation research

protocol synopsis couples will be invited to take part in the study by their healthcare provider (hcp). the couple will enrol via an online portal, complete an education module, provide consent and complete a questionnaire. those who consent to carrier screening will be sent mouth swab kits with samples returned by mail.the carrier screening performed will be done via accredited testing laboratories in partnership with clinical genetics services. genetic counselling will be available to study participants throughout the process. couples at increased risk will be offered a genetic counselling consultation and offered support to access reproductive options (i.e. prenatal diagnosis, preimplantation genetic diagnosis (pgd) which will be funded by the study for one cycle of ivf with pgd). all participants will be asked to complete an initial survey at study enrolment and invited to complete optional surveys at the time of screening, after return of screening results, and approximately 13 to 19 months after results. subsets of participants will also be invited to take part in interviews. gene list for carrier screening the approximately 1300 genes tested in the mackenzie's mission carrier screening panel meet the following criteria: 1. the associated condition is one where an 'average' couple would take steps to prevent the birth of a child with that condition. - this includes conditions with significant negative impact on quality of life for the child, the condition being lethal in childhood, and a significant impact on the family. 2. and/or: there is a potential benefit for knowing about the condition to inform management in the neonatal period. this criterion was particularly important if the condition was either not included on a newborn screening panel, and/or intervention would be required prior to results from newborn screening being known. 3. and there is strong evidence for mutations in the gene being causative of the condition in question, with enough variants reported to allow confidence in informing couples of their chance of having a child with the condition in question.

Eligibility criteria:
in order to take part in the study, couples need to have visited a recruiting hcp who will assess them for eligibility based on the criteria below: inclusion criteria * planning to become pregnant or in early pregnancy (less than 10 weeks gestation at enrolment and less than 11 weeks gestation at sample receipt by the laboratory) * both members of the couple available to participate in the study and available to provide a sample for testing at the same time. * if the couples are using an egg/sperm donor/s, the donor/s need to be available to provide a dna sample for testing and consent to having carrier screening. nb: if both members of the couple are known carriers of the same autosomal recessive condition, or the female is a known carrier of an x-linked recessive condition, they will still be eligible to have rgcs through the study, but will only be considered an 'increased-risk' couple for the purposes of this study if they are identified through the study testing to be carriers of pathogenic variants in a different gene. exclusion criteria participating couples meeting any of the following requirements will be excluded from this study: * pregnant and greater than 10 weeks gestation at enrolment. * only one member of the couple agrees to participate in the study. * one or both members of the couple are less than 18 years old. * both members of the couple are not available to be tested at the same time. * the couple are using an egg/sperm donor/s and the donor/s are not available for testing or the couple are using an anonymous donor. * one member of the couple has already been screened as part of the study.

Keywords: reproductive genetics carrier screening rare disease