Conditions such as Severe Congenital Neutropenia (SCN) 1, Hypertrophic Cardiomyopathy 2, 3, Autosomal Dominant Cerebellar Ataxia (ADCA), Opitz Syndrome, Neurofibromatosis type 1 (NF 1), Autosomal recessive Polycystic Kidney Disease (ARPKD), Congenital adrenal hyperplasia (CAH), and Phenylketonuria (PKU) have been reported in offspring originating from gamete donation (82). Although these events are not numerous, they show the need to consider the potential of genetic disease transmission using donor gametes. Gametes are the only cells that carry such genetic material, which could potentially affect the recipient (offspring) with any genetic disease. Information should be shared with women/couples requesting this service/treatment, as any donor could be a potential carrier of a genetic disease.
One could argue that the number of children born with a genetic disease that are conceived through Assisted Reproduction Technology (ART) and gamete donation is probably larger than reported since couples are reluctant to reveal or share information regarding the method of conception and the use of a donor gametes. Also, the fact that a large percentage of couples resorting to cross border care opt for the use of donated gametes.
According to the European Directives on Tissues and Cells the donor’s medical history must be assessed and genetic testing be applied if required. Screening could be targeted and certainly applied in situations where any serious autosomal or recessive genetic disease has prevalence more than 1:5000 (a carrier frequency of 3%) e.g. Beta Thalassaemia in the Mediterranean population, Cystic fibrosis in Caucasians and Familial Mediterranean Fever in the Middle East.
The following questions arise:
i) Should the transmission of a genetic illness from a gamete donor be considered as a Serious Adverse Reaction?
ii)Should there be systems for the reporting of such transmissions to regulators?
Given that in most of the cases reported and documented in the NOTIFY database, it would have been very difficult, or impossible, to have identified the risk in advance of the initial donation, it might be argued that these tragic occurrences will inevitably happen on rare occasions. It is very important to note, however, that in many of the cases reported, where the sperm donor was the source of the genetic defect, the sperm bank continued to supply sperm from that donor, without knowing about, or without taking account of, a genetic transmission that had occurred. The result was multiple children affected by the same genetic defect. For example, in a case of SCN transmitted by a sperm donor, 5 children were born with the defect1. Another donor transmitted Hypertrophic Cardiomyopathy to 9 children. In the early years of ART, a single donor, whose sperm was used to create 42 children, was shown to carry the gene for Opitz Syndrome, with a 50:50 chance of inheritance. The first affected child was conceived just before the Human Fertilisation and Embryology Authority (HFEA) was created in 1991 in the UK; the regulator restricted to 10 the number of offspring from one donor.
It is these cases of multiple affected offspring that highlight the value of vigilance reporting of genetic transmissions by ART. In some cases the condition is diagnosed immediately after birth or early in the life of the child. In these cases, if a serious adverse reaction report was made, it could prevent further use of the sperm and the birth of further children with the same condition. In some cases, the condition manifests itself only years after puberty so an SAR report will be too late to prevent further use of the sperm. For example, sperm from a donor with ADCA was used for the conception of 18 children in 13 women. Half of the children would have inherited the gene but it would not have been detected in the offspring until after puberty. In this case, the donor himself was the first to manifest the condition and an immediate serious adverse event report might have prevented further use of the sperm.
One of the challenges of notification, either by the families of affected children or by donors, is the secrecy that often surrounds gamete donation and the use of ART to conceive. Genetic conditions are diagnosed in children in specialist units and may never be communicated to the sperm bank or to the clinic where an oocyte donation was performed. This is complicated by the degree to which couples travel to other countries for ART, usually due to restrictive laws in their own country. There are no international registries of gamete donors.
1. The birth of a child with a genetic illness following donation of gametes or embryos should be reported as a suspected serious adverse occurrence. It should be investigated as such so that further gametes, or embryos created from that donor’s gametes, are not used without confirmation that they do not carry the gene(s) or chromosomal abnormality. It is important to check whether the condition could have arisen from a genetic abnormality in the non-donor partner e.g. possible oocyte origin if the offspring were conceived using donor sperm.
2. The diagnosis of a genetic condition in an adult who has previously donated gametes or embryos should be reported as an adverse occurrence implying risk of harm so that stored gametes or stored embryos created from that donor’s gametes, are not used without confirmation that they do not carry the gene(s) or chromosomal abnormality.
3. Sperm banks should have access to clinical genetic expertise for advice in developing donor screening policies and in investigating suspected genetic transmissions to offspring.
To facilitate the effectiveness of vigilance reporting in these circumstances, the following is recommended:
• Couples having ART treatment with donated gametes or embryos should be strongly advised to inform any doctors subsequently treating the resulting child(ren) of the donor origin. They should understand that, in the unlikely event that a child will manifest an inherited condition, informing the clinic could protect other families. Consideration could be given to the development of a carefully worded standard leaflet explaining these issues that could be provided to all couples.
• Gamete and embryo donors should be strongly advised to inform the clinic where they donated, in the event that they are subsequently diagnosed with any genetic condition. In this case also, a standard information leaflet for donors might be considered. In the analogous situation of allogeneic cord blood banking, some banks provide the donor mother with a leaflet asking her to contact the bank in the unlikely event that the donor child manifests a genetic or other illness, so that the transmission of the illness by transplantation of the cord blood can be prevented.
• Specialist genetic centres should always consider whether a child manifesting a genetic condition might have been conceived with donor gametes or embryos. This issue should be raised immediately and openly with the parents in the interests of other potential offspring and when parents acknowledge the involvement of a donor, they should be strongly urged to contact the ART Centre. The issue should be included in the appropriate professional standards and guidance for specialist genetic centres.
• Consideration should be given to the establishment of international registries of gamete and embryo donors so that contact can be more easily maintained for the purposes of vigilance and, in the case of oocyte donors, donor follow-up.