Genetic consequences of serial sperm donation

Study questionHow does serial sperm donation impact genetic risk in the donor-conceived children and their descendants? Summary answerIn addition to the psychological effects of serial sperm donation, donor-conceived children are at risk of unintentional inbreeding. This risk is compounded by the hard-to-quantify effect of social proximity between mothers. Such inbreeding would cause children to have up to 15% excess risk of childhood mortality or congenital morbidities. The risk to descendants after many generations is spread across many individuals and remains low as long as the number of donor-conceived children does not increase appreciably. What is known alreadyInbreeding increases the risk for a range of diseases among the offspring, with the risk increasing with the degree of inbreeding. Sperm donation increases the risk of accidental inbreeding, and thus likely increases disease risk. Study design, size, durationWe performed a literature review of risks associated with consanguinity across a range of traits, together with a model-based mathematical analysis to estimate the short- and long-term risk associated with serial sperm donation. Participants/materials, setting, methodsWe used whole-genome sequencing and imputed sequence data from the CARTaGENE longitudinal study to estimate population prevalence of relevant risk alleles. We performed mathematical modelling based on these results on published estimates of the risk associated with inbreeding. Main results and the role of chanceWith over 600 children conceived in this serial sperm donation event, 0.1 consanguineous unions would be expected under the simplest model of random mating by generation within the province of Quebec. Preferential mating due to geographic and social proximity among the mothers could increase this rate appreciably, so that accidental inbreeding is not unlikely. Since the likelihood of inbreeding events increases quadratically with the number of children, active inbreeding avoidance by the offspring and interventions to reduce continued serial donation can reduce risk. Over generations, more distant inbreeding is unavoidable, but inbreeding coefficients are reduced. Our model predicts that the long-term excess number of serious adverse events will be fewer than one per generation. The short- and long-term rates of specific diseases may be affected, however, given public information about the donor carrier status, we expect an excess of 0.84 children per generation [95% CI: 0,3] affected by Hereditary Tyrosinemia of type 1. Large scale dataCARTaGENE is a biobank based in Quebec, Canada, that is accessible following an independent data access protocol and can be found at: https://cartagene.qc.ca/en/ Limitations, reasons for cautionOur analysis relies on uncertain estimates of the burden associated with inbreeding. We also rely on simplifying assumptions about future events, including migrations, social interactions between mothers, and future sperm donation events. As a result, our estimates should be seen as coarse estimates. Wider implications of the findingsSerial sperm donation is not uncommon. Each documented instance has raised questions about the genetic burden associated with the practice. By quantifying this risk, this study will help inform the public health and genetic counselling response to these situations, in addition to being of interest from a population genetics perspective. Study funding/competing interest(s)This research was supported by the Canadian Institute for Health Research (CIHR) project grant 437576, NSERC grant RGPIN-2017-04816, the Canada Research Chair program to S.G., and the Canada Foundation for Innovation. T.M.Z was supported by the QLS Grad and Grad Excellence Award. The authors report no competing interests. ConsanguinityThe degree of relatedness between individuals, as measured by inheritance from recent ancestors. For example, second cousins share on average 3.125% of their DNA from their great-grandparents. InbreedingThe production of offspring from individuals with high consanguinity. Runs of Homozygosity (ROH)Stretches of the genome where identical alleles were received from both parents. The fraction of the genome in ROH is a measure of inbreeding. Donor-Conceived Child (DCC)Child born following sperm donation. DCC(X) refers to a child born following sperm donation by individual X. Congenital MorbidityDiseases or medical conditions present from birth, including physical, intellectual, or developmental. Specifically, does not include any diseases or conditions that arise from exposure to medications or chemicals during gestation or infections during pregnancy.