Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children.

AIMS: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. METHODS: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. RESULTS: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as "pathogenic" based on clinical observation and 66 with a high likelihood of causing gene dysfunction. CONCLUSION: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now available and affordable, but industry practice must be modified to incorporate its use.

Stability of selected serum hormones and lipids after long-term storage in the Janus Serum Bank.

BACKGROUND: The potential value of a biobank depends on the quality of the samples, i.e. how well they reflect the biological or biochemical state of the donors at the time of sampling. Documentation of sample quality has become a particularly important issue for researchers and users of biobank studies. OBJECTIVE: The aim of this study was to investigate the long-term stability of selected components: cholesterol, high density cholesterol (HDLC), low density cholesterol (LDLC), apolipoprotein A1 (apo-A1), apolipoprotein B (apo B), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH) and free thyroxin (FT4). DESIGN AND METHODS: Samples, stored at -25°C, from 520 men aged 40-49 years at blood sampling distributed in equally sized groups (n=130) according to length of storage, 0, 4, 17 and 29 years, respectively, were used in a cross sectional design. The freshly collected serum samples were used as a reference group to calculate storage related changes. RESULTS: The differences between fresh samples and samples stored for 29 years were substantial for apo-A1 (+12%), apo-B (+22.3%), HDLC (-69.2%), LDLC (+31.3%), and PRL (-33.5%), while total cholesterol, FSH, LH, TSH and FT4 did not show any significant difference. CONCLUSIONS: The study showed large differences in serum level of the selected components. The lipids and apolipoproteins were all changed except for total cholesterol. Most hormones investigated (FSH, LH, TSH and FT4) proved to be stable after 29 years of storage while PRL showed sign of degradation. The observed differences are probably due to long-term storage effects and/or external factors (i.e. diet and smoking).

The ownership that wasn't meant to be: Yearworth and property rights in human tissue.

This paper is concerned with the English Court of Appeal's decision in Yearworth v North Bristol NHS Trust that six men had, for the purposes of their claims against the trust, ownership of the sperm they had produced. The case has been discussed by many commentators and most, if not all, of those who have discussed the case have claimed or assumed that the court held that the claimants had property rights in the sperm they had produced. In this paper, I advance an interpretation of the case that does not regard the court as deciding that the men had property rights (in the narrow sense of that term) in the sperm they had produced. On this view, the 'ownership' that the Court of Appeal purported to vest in each of the men was not a right in rem, a right 'binding the world'. If this is so, it is perhaps unsurprising that some scholars, evaluating the success of the court's reasoning as a justification for vesting the claimants with property rights, have found it to be unsatisfactory.

Cytomegalovirus and human immunodeficiency virus in semen of homosexual men.

OBJECTIVE: To assess the accuracy of serology to predict the presence of cytomegalovirus (CMV) in semen of homosexual men without and with HIV coinfection. DESIGN: Semen CMV was detected by electron microscopy and by polymerase chain reaction (PCR) amplification; paired serum was tested for CMV IgG/IgM. Semen HIV was detected by reverse transcription-PCR. SETTING: Licensed clinical and research laboratory. PATIENT(S): Sixty-eight men. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency of CMV and HIV in semen. RESULT(S): Cytomegalovirus was detected by electron microscopy in 3 of 10 specimens examined. Forty-six (89%) of 52 HIV-infected men were seropositive for CMV by combined assay for IgG/IgM; two more (48 of 52, 92%) were seropositive for CMV IgG by separate assay; 25 (48%) of the HIV-infected men had PCR-detectable CMV DNA in at least one semen specimen, 22 of whom (42%) had CMV in all specimens. Nineteen (13%) of the 150 specimens tested positive for HIV, whereas 67 (45%) tested positive for CMV; seven specimens tested positive for both CMV and HIV. Cytomegalovirus, but not HIV, detection in semen correlated with decreased CD4(+) lymphocytes in peripheral blood (<700/µL) but was not accurately predicted by serology, leukocytospermia, or age. CONCLUSION(S): Cytomegalovirus in semen is not accurately predicted by serology. Sperm banking needs to include direct assessment of CMV in semen specimens. Strategies to eliminate CMV from semen specimens are needed to alleviate the risk of virus transmission.

Clinical guidelines for sperm cryopreservation in cancer patients.

No clear clinical guidelines exist on how to counsel male cancer patients about fertility preservation. Detailed counseling is recommended before treatment when issues of collection and storage need to be highlighted. Concern about the quality of sperm collected before and/or after treatment in terms of assisted reproduction is needed, and the potential outcomes should be discussed early as part of cancer survivorship. The discussion should be sensitive and tailored to the ethical situation based on the age of the patient, the severity of the illness, the need to initiate treatment, and genetic risk. Cryopreservation should be attempted/achieved before cancer treatment is initiated. Cryopreservation should not be performed during treatment or for some time after treatment because of the chromosomal and structural damage to sperm from cancer treatment. Contraception should be instigated during this period.

Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility.

OBJECTIVE: To evaluate the clinical utility of genetic testing for cystic fibrosis (CF) and spinal muscular atrophy (SMA) in sperm donors. STUDY DESIGN: We studied the results of the genetic tests for CF and SMA applied to 372 sperm donor candidates. The CF carrier screening test analysed 32 mutations on the CFTR gene. Regarding SMA, the carrier test studied possible deletions of SMN1/2 by Multiplex Ligation-dependent Probe Amplification (MLPA) methodology. RESULTS: The carrier frequency obtained was greater for SMA than for CF. After adjusting the results obtained for the sensitivity of the tests, and taking into account the prevalence of female carriers in our population, the probability of transmission of the disease to the child from a donor with a negative genetic test was about five times lower in the case of SMA than in CF, although this difference was not statistically significant. The number of donors needed to screen (NNS) to avoid the occurrence of a child being affected by CF and SMA in our population was similar in both cases (1591 vs. 1536). CONCLUSIONS: This study demonstrates the need to include SMA among the diseases for which genetic screening is performed in the process of sperm donor selection. We believe that testing donors for SMA is as important and as useful as doing so for CF.

Genetic evaluation procedures at sperm banks in the United States.

OBJECTIVE: To assess how genetic evaluations of sperm donor applicants are performed in the United States. DESIGN: A questionnaire was designed to assess: 1) the professionals involved in the family history evaluation and genetic screening; 2) the genetic testing, counseling, and informed consent processes; and 3) how the results of genetic evaluations and new risk information is communicated to donors. SETTING: Semen donor facilities. PARTICIPANT(S): Representatives of semen donor facilities. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Descriptive data. RESULT(S): Thirteen responses were received. All of the facilities assessed donors' family histories; eight of the facilities (62%) routinely informed donors about the results of these evaluations. At the majority of facilities (10/13), informed consent for genetic testing is obtained as part of the overall contract to be a sperm donor. Genetic counselors are employed full-time at two facilities and part-time at five others. CONCLUSION(S): There is variability in the education and informed consent processes for semen donor applicants, including variable communication about the limitations of genetic tests and the potential implications for the donors' own children. Further research into the best practices for education and consent for sperm donor applicants may be beneficial to ensure the well-being of the donors and their future offspring.

Recommendations for gamete and embryo donation: a committee opinion.

This document provides the latest recommendations for evaluation of potential sperm, oocyte, and embryo donors, incorporating recent information about optimal screening and testing for sexually transmitted infections, genetic diseases, and psychological assessments. This revised document incorporates recent information from the U.S. Centers for Disease Control and Prevention, the US Food and Drug Administration, and the American Association of Tissue Banks, with which all programs offering gamete and embryo donation services must be thoroughly familiar, and replaces the document titled, "2008 Guidelines for Gamete and Embryo Donation: A Practice Committee Report," last published in Fertil Steril 2008;90:S30-44.

Gamete donation in France: the future of the anonymity doctrine.

In France, since the approval of the first bioethics laws in 1994, the principle of the anonymity of sperm donors has prevailed. This choice is regularly challenged, namely by children who have been conceived under these conditions and have now reached adulthood. In this paper, we will briefly describe the reasons that led practitioners of assisted reproduction to endorse the anonymity principle in 1994. Secondly, we will elaborate on the reasons why this principle is becoming so controversial today. Finally, we shall examine two possible outcomes of the debate, highlighting their respective legitimacy as well as their consequences, as far as the rights of children, the notion of the family, and medical practice are concerned.

Fertility clinic, egg donation agency, and sperm bank policies.

OBJECTIVE: To assess the level of openness in U.S. gamete donation policies across fertility clinics, egg donation agencies, and sperm banks. DESIGN: Primarily a content analysis of organizational materials (e.g., websites, brochures). SETTING: Not applicable. PARTICIPANT(S): A total of 219 fertility clinics, 100 egg donation agencies, and 30 sperm banks. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Use of donor photographs, anonymity between parties, cycle outcome disclosure, and postcycle contact. RESULT(S): Agencies were more likely to provide donor photographs, have proactive policies to inform donors of the cycle outcome, and have nonanonymous options compared with sperm banks and clinics. Sperm banks were more likely to offer institutionalized donor identity-release programs. CONCLUSION(S): Clinics, agencies, and sperm banks have different policies to address the level of openness between donors, recipients, and donor-conceived children. Although agencies generally offer more open arrangements, only a minority of organizations restricted all types of contact and communication between parties.

Lost property? Legal compensation for destroyed sperm: a reflection and comparison drawing on UK and French perspectives.

In a recent case in the UK, six men stored their sperm before undergoing chemotherapy treatment for cancer in case they proved to be infertile after the treatment. The sperm was not properly stored and as a result was inadvertently destroyed. The men sued the NHS Trust that stored the sperm and were in the end successful. This paper questions the basis on which the judgement was made and the rationale behind it, namely that the men 'had ownership' of the sperm, and that compensation was thus due on the grounds that the men's property had been destroyed. We first argue that the claim is erroneous and enhances the tendency towards the commodification of body parts. We then suggest that the men could have been compensated for the harm done to them without granting property rights, and that this would, at least in philosophical and ethical terms, have been more appropriate. To help illustrate this, we draw on a parallel case in French law in which a couple whose embryos had been destroyed were overtly denied ownership rights in them. Finally, we suggest some possible ethical and practical problems if the proprietary view expressed in the UK ruling were to become dominant in law, with particular focus on the storing of genetic information in biobanks. We conclude that, although compensation claims should not necessarily be ruled out, a 'no property in the body' approach should be the default position in cases of detached bodily materials, the alternative being significantly ethically problematic.

Yearworth v. North Bristol NHS trust: a property case of uncertain significance?

It has long been the position in law that, subject to some minor but important exceptions, property cannot be held in the human body, whether living or dead. In the recent case of Yearworth and Others v North Bristol NHS Trust, however, the Court of Appeal for England and Wales revisited the property debate and threw into doubt a number of doctrines with respect to property and the body. This brief article analyses Yearworth, (1) reviewing the facts and the Court's decision with respect to the originators' proprietary and contractual interests in their body and bodily products, (2) considering the significance of relying on property and its use a legal metaphor, (3) questioning the scope of the property right created, and (4) querying whether an alternate conceptual approach to extending rights and a remedy was warranted. It concludes that, while Yearworth engages with, and impacts on, important theoretical and practical issues--from legal, healthcare and research perspectives--it does not offer a great deal of guidance and, for that reason, its precedential significance is in doubt.

Genetic testing of sperm donors: survey of current practices.

OBJECTIVE: To determine which genetic tests are being performed on sperm donor applicants in the United States. DESIGN: An electronic survey was distributed to 26 sperm banks to evaluate their genetic testing practices. SETTING: Sperm banks in the United States. PATIENT(S): Not applicable. INTERVENTION(S): None. Survey of current practices. MAIN OUTCOME MEASURE(S): Survey of current practices. RESULT(S): Cystic fibrosis (CF) carrier screening, chromosome analyses, and hemoglobin evaluations are performed on the majority of sperm donor applicants. Tay-Sachs disease carrier screening is performed on most donors with Jewish heritage but there is significant variation in screening for other disorders that occur with increased frequency in this population. Individual sperm banks use different laboratory tests for evaluation of the same conditions, with each test having different carrier detection rates and interpretations. CONCLUSION(S): The genetic testing performed on sperm donors varies significantly at sperm banks across the United States. Therefore, recipients should be clearly informed about the specific evaluations performed on their donor of interest. Thus it is important that sperm banks employ genetic professionals to evaluate the donors' and recipients' medical histories and perform a genetic risk assessment. This will allow clients to make informed decisions about use of semen specimens from an anonymous sperm donor.

Implications of hypertrophic cardiomyopathy transmitted by sperm donation.

CONTEXT: Sperm donation is an increasingly common practice for achieving pregnancy in the absence of a male partner or when fertility is problematic. The unintended consequence in which genetic diseases are unwittingly transmitted to offspring is an underrecognized public health issue not previously prioritized by US Food and Drug Administration guidelines. OBJECTIVE: To report the clinical circumstances and implication of hypertrophic cardiomyopathy (HCM) transmitted by sperm donation to recipients. SETTING: Voluntary sperm donation through a US Food and Drug Administration-approved tissue bank. MAIN OUTCOME MEASURE: Incidence of genetically affected offspring and clinical outcomes to date. RESULTS: An asymptomatic 23-year-old man who had no personal knowledge of underlying heart disease and who underwent standard testing that was negative for infectious diseases, repeatedly donated sperm over a 2-year period (1990-1991). The donor was later shown to be affected (in 2005) by a novel beta-myosin heavy-chain mutation that caused HCM, after an offspring was clinically diagnosed with this disease. Of the 24 children known to be offspring of the donor, including 22 who were products of fertilization via sperm donation and 2 conceived by the donor's wife, a total of 9 genetically affected offspring, 2 to 16 years of age and 6 males, have been identified with HCM (2005-2009). Three of the 9 gene-positive children have currently expressed phenotypic evidence of HCM, including one who died at age 2 years due to progressive and unrelenting heart failure with marked hypertrophy, and also 2 survivors with extreme left ventricular hypertrophy at age 15 years. The latter 2 children and the donor are judged likely to be at increased risk for sudden death. CONCLUSIONS: This case series underscores the potential risk for transmission of inherited cardiovascular diseases through voluntary sperm donation, a problem largely unappreciated by the medical community and agencies regulating tissue donation. Recommendations include improved screening guidelines for donors to exclude cardiovascular diseases (eg, HCM) such as consideration for 12-lead electrocardiograms.

Who's keeping count? The need for regulation is a relative matter.

It is important to have an accurate model for calculating limits to sperm donation so as to avoid inadvertent half-sibling mating and help protect the rights and welfare of the donor- inseminated child. The most highly developed model to date cannot be used as there is inadequate regulation of donor insemination among United States sperm banks.