Outcomes of BRCA pre-implantation genetic testing according to the parental mutation origin: a cohort study.

BACKGROUND: The process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation. METHODS: This retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis. RESULTS: The cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively). CONCLUSIONS: BRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation.

Gendering the beginning of life: Taiwanese gay fathers' navigation of preimplantation genetic diagnosis-assisted sex selection in transnational third-party reproduction.

Preimplantation genetic diagnosis (PGD) has been used not only to avoid genetic diseases and increase conception success rates but also to perform non-medical sex selection, particularly in the surging cross-border reproductive care (CBRC). In the context of commercialised biomedicine, assisted reproductive technologies, such as lifestyle sex selection, have been tailored to meet intended parents' preferences. However, there is a lack of analysis on how individuals' reproductive decisions on PGD-assisted sex selection were shaped within the sociocultural norms and CBRC. This article explores Taiwanese gay fathers' navigations on sex selection while seeking third-party reproduction overseas because of local legal constraints. Drawing on in-depth interviews with 53 gay fathers (to-be), I analysed how 'individual preferences' were dynamically shaped by local sociocultural norms and embedded within transnational settings of routinising PGD in chosen repro-destinations. The findings showed that gay fathers mobilised strategic discourses on non-medical sex selection from both the local and the global to negotiate their decisions in coherence with their LGBTQ+ identity and their role as sons carrying familial responsibility to procreate male heirs. This article proposed a nuanced understanding of gay fathers' reproductive practices of 'gendering the beginning of life' through PGD-assisted sex selection.

Mapping ethical, legal, and social implications (ELSI) of preimplantation genetic testing (PGT).

PURPOSE: Preimplantation Genetic Testing (PGT) has attracted considerable ethical, legal, and social scrutiny, but academic debate often fails to reflect clinical realities. METHODS: Addressing this disconnect, a review of 506 articles from 1999 to 2019 across humanities and social sciences was conducted to synthesize the Ethical, Legal, and Social Implications (ELSI) of PGT. This review mined PubMed, WoS, and Scopus databases, using both MeSH terms and keywords to map out the research terrain. RESULTS: The findings reveal a tenfold increase in global research output on PGT's ELSI from 1999 to 2019, signifying rising interest and concern. Despite heightened theoretical discourse on selecting "optimal" offspring, such practices were scarcely reported in clinical environments. Conversely, critical issues like PGT funding and familial impacts remain underexplored. Notably, 86% of the ELSI literature originates from just 12 countries, pointing to a research concentration. CONCLUSION: This review underscores an urgent need for ELSI research to align more closely with clinical practice, promoting collaborations among ethicists, clinicians, policymakers, and economists. Such efforts are essential for grounding debates in practical relevance, ultimately steering PGT towards ethical integrity, societal acceptance, and equitable access, aiming to harmonize PGT research with real-world clinical concerns, enhancing the relevance and impact of future ethical discussions.

Preimplantation genetic testing in the current era, a review.

BACKGROUND: Preimplantation genetic testing (PGT), also referred to as preimplantation genetic diagnosis (PGD), is an advanced reproductive technology used during in vitro fertilization (IVF) cycles to identify genetic abnormalities in embryos prior to their implantation. PGT is used to screen embryos for chromosomal abnormalities, monogenic disorders, and structural rearrangements. DEVELOPMENT OF PGT: Over the past few decades, PGT has undergone tremendous development, resulting in three primary forms: PGT-A, PGT-M, and PGT-SR. PGT-A is utilized for screening embryos for aneuploidies, PGT-M is used to detect disorders caused by a single gene, and PGT-SR is used to detect chromosomal abnormalities caused by structural rearrangements in the genome. PURPOSE OF REVIEW: In this review, we thoroughly summarized and reviewed PGT and discussed its pros and cons down to the minutest aspects. Additionally, recent studies that highlight the advancements of PGT in the current era, including their future perspectives, were reviewed. CONCLUSIONS: This comprehensive review aims to provide new insights into the understanding of techniques used in PGT, thereby contributing to the field of reproductive genetics.

When Is Something an Alternative? A General Account Applied to Animal-Free Alternatives to Animal Research.

The first "R" from animal research ethics prescribes the replacement of animal experiments with animal-free alternatives. However, the question of when an animal-free method qualifies as an alternative to animal experiments remains unresolved.Drawing lessons from another debate in which the word "alternative" is central, the ethical debate on alternatives to germline genome editing, this paper develops a general account of when something qualifies as an alternative to something. It proposes three ethically significant conditions that technique, method, or approach X must meet to qualify as an alternative to Y: (1) X must address the same problem as Y, under an appropriate description of that problem; (2) X must have a reasonable chance of success, compared to Y, in solving the problem; and (3) X must not be ethically unacceptable as a solution. If X meets all these conditions, its relative advantages and disadvantages determine whether it is preferable, indifferent, or dispreferable as an alternative to Y.This account is then applied to the question of whether animal-free research methods qualify as alternatives to animal research. Doing so breaks down the debate around this question into more focused (ethical and other) issues and illustrates the potential of the account.

A critical view on using "life not worth living" in the bioethics of assisted reproduction.

This paper critically engages with how life not worth living (LNWL) and cognate concepts are used in the field of beginning-of-life bioethics as the basis of arguments for morally requiring the application of preimplantation genetic diagnosis (PGD) and/or germline genome editing (GGE). It is argued that an objective conceptualization of LNWL is largely too unreliable in beginning-of-life cases for deriving decisive normative reasons that would constitute a moral duty on the part of intending parents. Subjective frameworks are found to be more suitable to determine LNWL, but they are not accessible in beginning-of-life cases because there is no subject yet. Conceptual and sociopolitical problems are additionally pointed out regarding the common usage of clear case exemplars. The paper concludes that a moral requirement for the usage of PGD and GGE cannot be derived from the conceptual base of LNWL, as strong reasons that can be reliably determined are required to limit reproductive freedom on moral grounds. Educated predictions on prospective well-being might still be useful regarding the determination of moral permissibility of PGD and/or GGE. It is suggested that due to the high significance of subjective experience in the normativity of beginning-of-life bioethics, the discipline is called to more actively realize the inclusion of people with disabilities. This regards for instance research design, citation practices, and language choices to increase the accessibility of societal debates on the reproductive ethics of genetic technologies.

[Ethical Reflections on Preimplantation Genetic Diagnoses].

With fertility rates at an all-time low, children have become even more the 'treasures' of their families. Progress in genetic selection technology has made preimplantation genetic diagnosis an increasingly common practice in clinics. However, the practice of purposively selecting genes for future children remains controversial. In this article, the process of preimplantation genetic diagnosis is introduced and related philosophical and social perspectives are reviewed. Finally, the ethics related to this practice are discussed in the contexts of obligation theory, utility theory, and four ethical principles. The authors hope this article sheds light on the diverse perspectives used to consider and discuss the ethical issues surrounding gene selection and, importantly, helps nurses provide care grounded in ethics and humanity in ethically uncertain circumstances.

BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling.

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. It includes three different types; SHFLD1 (MIM % 119,100), SHFLD2 (MIM % 610,685) and SHFLD3 (MIM # 612576). The latter was shown to be the most commonly reported with a duplication in the 17p13.1p13.3 locus that was narrowed down to the BHLHA9 gene. Here, we report a consanguineous Lebanese family with three members presenting with limb abnormalities including tibial hemimelia. One of these patients presented with additional bowing fibula and another with bilateral split hand. CGH array analysis followed by RQ-PCR allowed us to detect the first homozygous duplication on the short arm of chromosome 17p13.3 including the BHLHA9 gene and involved in SHFLD3. Interestingly, one patient with the homozygous duplicated region, carrying thus four BHLHA9 copies presented with long bone deficiency but no SHFM. The incomplete penetrance and the variable expressivity of the disease in this family as well as the presence of the BHLHA9 homozygous duplication rendered genetic counseling extremely challenging and preimplantation genetic diagnosis almost impossible.

Assessment of attitudes towards the use of preimplantation genetic diagnosis in a single center in Riyadh, Saudi Arabia.

In this cross-sectional study, we assessed the attitudes of the general public in Saudi Arabia regarding both medical and non-medical applications of pre-implantation genetic diagnosis (PGD). The study was conducted in King Abdullah Specialist Children's Hospital (KASCH) in Riyadh with a sample size of 377. Demographic information was collected, and attitudes towards applications of PGD were assessed using a pre-validated self-administered questionnaire. Out of the total sample size, 230 (61%) were males, 258 (68%) were married, 235 (63%) had one child or more, and 255 (68%) were older than 30 years of age representing the majority of participants. Only 87 (23%) of participants reported prior experience with PGD. Personally, knowing someone who had a prior experience with PGD was associated with higher attitude scores (more favorable attitudes towards PGD) (p-value = 0.04). The findings of this study indicate that our sample of Saudi individuals generally had a positive attitude towards the use of PGD.

Novel economical, accurate, sensitive, single-cell analytical method for mitochondrial DNA quantification in mtDNA mutation carriers.

PURPOSE: Although a variety of analytical methods have been developed to detect mitochondrial DNA (mtDNA) heteroplasmy, there are special requirements of mtDNA heteroplasmy quantification for women carrying mtDNA mutations receiving the preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PD) in clinic. These special requirements include various sample types, large sample number, long-term follow-up, and the need for detection of single-cell from biopsied embryos. Therefore, developing an economical, accurate, high-sensitive, and single-cell analytical method for mtDNA heteroplasmy is necessary. METHODS: In this study, we developed the Sanger sequencing combined droplet digital polymerase chain reaction (ddPCR) method for mtDNA quantification and compared the results to next-generation sequencing (NGS). A total of seventeen families with twelve mtDNA mutations were recruited in this study. RESULTS: The results showed that both Sanger sequencing and ddPCR could be used to analyze the mtDNA heteroplasmy in single-cell samples. There was no statistically significant difference in heteroplasmy levels in common samples with high heteroplasmy (≥ 5%), low heteroplasmy (< 5%), and single-cell samples, either between Sanger sequencing and NGS methods, or between ddPCR and NGS methods (P > 0.05). However, Sanger sequencing was unable to detect extremely low heteroplasmy accurately. But even in samples with extremely low heteroplasmy (0.40% and 0.92%), ddPCR was always able to quantify them. Compared to NGS, Sanger sequencing combined ddPCR analytical methods greatly reduced the cost of sequencing. CONCLUSIONS: In conclusion, this study successfully established an economical, accurate, sensitive, single-cell analytical method based on the Sanger sequencing combined ddPCR methods for mtDNA heteroplasmy quantification in a clinical setting.

Evaluation of non-invasive gene detection in preimplantation embryos: a systematic review and meta-analysis.

BACKGROUND: Genetic abnormalities in embryos are responsible for most miscarriages and repeated embryo implantation failures, so a reliable preimplantation genetic screening method is urgently needed. Non-invasive preimplantation genetic testing (niPGT) is a potential method for embryo genetic diagnosis. However, the value of its application is controversial. This meta-analysis aimed to investigate and validate the diagnostic value of niPGT in patients undergoing in vitro fertilization (IVF). METHODS: This review used the "Preferred Reporting Items" as a systematic review and meta-analysis of the diagnostic test accuracy (PRISMA-DTA) statement. We searched PubMed, Embase, Web of Science Core Collection, and Cochrane Library up to May 2022 to retrieve non-invasive preimplantation gene detection studies. The eligible research quality was evaluated following the quality assessment study-2 system for diagnostic accuracy. The pooled receiver operator characteristic curve (SROC) and the area under SROC (AUC) were used to evaluate diagnostic performance quantitatively. Threshold effect, subgroup analysis, and meta-regression analysis were used to explore the source of heterogeneity. Deeks' funnel plots and sensitivity analyses were used to test the publication bias and stability of the meta-analysis, respectively. FINDINGS: Twenty studies met the inclusion criteria. The pooled sensitivity, specificity, and AUC were 0.84 (95% CI 0.72-0.91), 0.85 (95% CI 0.74-0.92), and 0.91 (95% CI 0.88-0.93), respectively. Subgroup analysis showed that the spent culture medium (SCM) subgroup had higher sensitivity and lower specificity than the SCM combined with the blastocoel fluid (BF) subgroup. Subgroup analysis showed that the study sensitivity and specificity of < 100 cases were higher than those of ≥ 100. Heterogeneity (chi-square) analysis revealed that sample size might be a potential source of heterogeneity. Sensitivity analysis and Deeks' funnel plots indicated that our results were relatively robust and free from publication bias. INTERPRETATION: The present meta-analysis indicated that the pooled sensitivity, specificity, and AUC of niPGT in preimplantation genetic testing were 0.84, 0.85, and 0.91, respectively. niPGT may have high detection accuracy and may serve as an alternative model for embryonic analysis. Additionally, by subgroup analysis, we found that BF did not improve the accuracy of niPGT in embryos. In the future, large-scale studies are needed to determine the detection value of niPGT.

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions.

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20-22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11-14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important.

Regulating non-invasive prenatal testing (NIPT) for fetal sex determination.

Non-invasive prenatal testing (NIPT) can be used to determine the chromosomal sex of the fetus at an early stage in a pregnancy. The use of NIPT for fetal sex determination raises concerns about potential selective termination of pregnancy by prospective parents who desire a child of a particular sex. Although sex selection for medical reasons is generally accepted, non-medical sex selection (NMSS) has been the subject of considerable controversy. In this article, we explore the current regulatory landscape around reproductive genetic testing techniques that may lead to NMSS, both internationally and within Australia. Specifically, we contrast the approach to regulating preimplantation genetic testing (PGT) with the minimal regulation of NIPT in Australia as a case study for reform. We examine ethical concerns raised in relation to NMSS, which form the basis of the current moratorium on the use of PGT for NMSS. We then highlight some key differences between using PGT for NMSS and NIPT for fetal sex determination to determine whether access to the latter should be regulated and, if so, how. We conclude that there is insufficient evidence to restrict access to NIPT for fetal sex determination and, based on our Australian case study, recommend a facilitative approach to regulating NIPT that would support individuals to make informed reproductive decisions.

Ethical and moral perspectives of individuals who considered/used preimplantation (embryo) genetic testing.

This study examined perspectives on the ethical implications of preimplantation genetic testing (PGT) among individuals who actually (not hypothetically) used or considered using PGT. Most of the prior patient-centered research on PGT ethics used qualitative designs (9 out of the 11 articles) and focused only on single gene testing. This cross-sectional study used an anonymous online questionnaire; 15 items assessed potential ethical concerns involved in PGT decision-making, including clinical indications for PGT, the greater implications of PGT for society, and unused embryo disposition. N = 207 individuals (mean female/male age 35.7/38.9 years, 21% Hispanic or non-White) who had recently used or considered using PGT for single gene (60%) or for chromosomal testing (40%) completed the questionnaire. Most respondents supported PGT screening for disease conditions with childhood or adult onset that are untreatable (64%-85% across items); most opposed PGT for trait selection (76%-81%). Most respondents agreed that PGT aids in parental decision-making (66%-67%), although some expressed concern over potential unforeseen consequences (25%-30%). Regarding disposition of embryos without known genetic abnormalities, most respondents favored freezing indefinitely (86%) or donating to another family (69%), while for embryos with genetic abnormalities, most respondents favored donating to research (78%) or destroying them (62%). Stratification by religious affiliation revealed several differences, such as less acceptance of PGT for diseases that occur in adulthood and have no treatment options among Protestants (p = .015) and greater willingness to donate surplus embryos to research among participants without a religious affiliation (p < .001). These results are limited by the relatively homogeneous sample of participants (mostly White, married, and predominantly college-educated). In summary, participants who considered/used PGT found PGT acceptable overall for screening for disease conditions; most opposed using PGT for trait selection. Our novel questionnaire provides a structured tool for assessing the ethical perspectives surrounding the use of PGT.

A qualitative interview study of the attitudes toward reproductive options of people with genetic visual loss.

In the United Kingdom (U.K), 2.19 million people are affected by visual loss. Monogenic causes of visual loss include retinal dystrophies, optic neuropathies, and congenital glaucoma. A variety of reproductive options are available to adults with genetic visual loss to permit them to have an unaffected child. Prenatal diagnostic testing (PND) via amniocentesis or chorionic villus sampling (CVS) or Preimplantation Genetic Testing (PGT) is possible, provided the causal genetic variants are known in the family. We report a qualitative interview study of people with genetic causes of visual loss to explore their attitudes toward reproductive options. Participants reported a range of challenges associated with living with genetic conditions associated with visual loss. These had the potential to shape attitudes to reproductive options. Participants expressed enthusiasm for genetic testing, as it enabled them to understand if relatives might be affected by the visual loss. Decisions around reproductive options were recognized as challenging and highly personal. Positive opinions of PGT were reported, as it permitted conception of a child without the genetic cause of visual loss while avoiding the need for the termination of pregnancy. The provision of accessible information resources on genetics and reproductive options was reported to be important.

Embryo biopsy and perinatal outcomes of singleton pregnancies: an analysis of 16,246 frozen embryo transfer cycles reported in the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System.

BACKGROUND: Preimplantation genetic testing is commonly performed by removing cells from the trophectoderm, the outer layer of the blastocyst, which subsequently forms the placenta. Because preimplantation genetic testing removes the cells that are destined to form the placenta, it is possible that preimplantation genetic testing could be associated with an increased risk for adverse outcomes associated with abnormal placentation. Despite the increasing utilization of preimplantation genetic testing, few studies have investigated the perinatal outcomes, with published studies yielding contradictory findings and using small sample sizes. OBJECTIVE: This study aimed to compare the perinatal outcomes of singleton pregnancies conceived following frozen embryo transfer of a single, autologous blastocyst either with or without preimplantation genetic testing. STUDY DESIGN: This was a retrospective analysis of autologous frozen embryo transfer cycles that led to singleton live births per the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System, including cycles initiated between 2014 and 2015. The perinatal outcomes, including birthweight, Z-score, small for gestational age, large for gestational age, macrosomia, and preterm birth, were compared between pregnancies with or without preimplantation genetic testing. We conducted multivariable linear regression analyses for the birthweight and Z-score and logistic regression for the binary outcomes. A false discovery rate was adjusted to decrease the type I error from multiple hypothesis testing. RESULTS: Of the 16,246 frozen embryo transfers resulting in singleton births included in this analysis, 6244 involved the transfer of a single blastocyst that had undergone preimplantation genetic testing, and the remainder (n=10,002) involved the transfer of a single blastocyst that had not undergone a biopsy. When compared with the women from the nonpreimplantation genetic testing group, the average maternal age (35.8±4.1 vs 33.7±3.9; P<.001) and prevalence of prior spontaneous abortion (37.3% vs 27.7%; P<.001) were higher among women from the preimplantation genetic testing group. Bivariate analysis revealed a higher prevalence of small-for-gestational-age newborns (4.8% vs 4.0%; P=.008) and premature delivery (14.1% vs 12.5%; P=.005) and a lower prevalence of large-for-gestational-age newborns (16.3% vs 18.2%; P=.003) and macrosomia (11.1% vs 12.4%; P=.013) among the preimplantation genetic testing pregnancies. Multivariate regression analyses, adjusting for the year of transfer, maternal age, maternal body mass index, smoking status (3 months before the treatment cycle), obstetrical histories (full-term birth, preterm birth, and spontaneous abortion), infertility diagnosis, and infant sex suggested a significantly increased odds of preterm birth (adjusted odds ratio, 1.20; 95% confidence interval, 1.09-1.33; P<.001) from preimplantation genetic testing blastocysts. Birthweight (-14.63; 95% confidence interval, -29.65 to 0.38; P=.056), birthweight Z-score (-0.03; 95% confidence interval, -0.06 to 0.00; P=.081), and odds of small-for-gestational-age newborns (adjusted odds ratio, 1.17; 95% confidence interval, 0.99-1.38; P=.066), large-for-gestational-age newborns (adjusted odds ratio, 0.96; 95% confidence interval, 0.88-1.06; P=.418), and macrosomia (adjusted odds ratio, 0.96; 95% confidence interval, 0.85-1.07; P=.427) did not differ between the frozen transfer cycles with or without preimplantation genetic testing in the analysis adjusted for the confounders. Subgroup analysis of the cycles with a stated infertility diagnosis (n=14,285) yielded consistent results. CONCLUSION: Compared with frozen embryo transfer cycles without preimplantation genetic testing, the frozen embryo transfer cycles with preimplantation genetic testing was associated with a small increase in the likelihood of preterm birth. Although the increase in the risk for prematurity was modest in magnitude, further investigation is warranted.

Family planning in carriers of BRCA1 and BRCA2 pathogenic variants.

BRCA1 and BRCA2 pathogenic variant carriers have a high lifetime risk of developing breast and ovarian malignancies. Given the risks and significant ramifications of undergoing risk-reducing surgeries, many pathogenic variant carriers unaffected by cancer (previvors) struggle with family planning and reproductive decision making. The objective of this study was to determine the attitudes and practices of BRCA1 and BRCA2 pathogenic variant carriers with respect to family planning decision making. A cross-sectional survey was conducted of BRCA1 and BRCA2 previvors at four Northeastern medical centers. The survey was administered electronically via email using REDCap. The survey included demographic information as well as questions about genetic testing, prophylactic surgeries, family planning, and partnering. Data were analyzed with Fisher's exact tests and t tests. The survey was completed by 139 of 422 BRCA1 and BRCA2 pathogenic variant carriers (response rate 33%). Thirteen were excluded from analysis due to self-reported cancer history. Of the remaining 126, 21 (16.7%) were male and 105 (83.3%) were female. Female participants <35 years old at the time of genetic testing were significantly more likely than those 35 or greater to report feeling urgency to have a family after finding out about their BRCA1 and BRCA2 pathogenic variant (p < 0.0001). Younger women also reported their genetic status had a stronger impact on their romantic relationships (p = 0.029). Men were significantly more likely to report that they felt no urgency to have a family compared to women (p < 0.0001). Our study reflects the complex decision making for previvors and the intricacies of family planning in this population. Providers can use this knowledge as a guide to counsel patients about reproductive options.

Exploring genetic counselors' use of pedigree symbols to represent assisted reproductive technology.

The standardized pedigree nomenclature recommendations created by the National Society of Genetic Counselors Pedigree Standardization Work Group contains some Assistive Reproductive Technology (ART) specific nomenclature. However, the work groups' recommendations lack instructions on how to document 'the number of embryos conceived, frozen, and implanted, along with their genetic testing history' (Bennett et al., 2008, p. 429). The purpose of this qualitative study was to determine if the current symbols are sufficient for what genetic counselors need in the ART field and how genetic counselors are addressing any gaps. Ten genetic counselors with ART counseling experience participated in semi-structured interviews. Participants reported using standard symbols and creating their own designs when standard symbols are not available for applicable ART situation. Thematic analysis identified seven reasons why participants felt that ART should be recorded on the medical pedigree. The 3 most common themes identified were: (1) medical assessment and facilitating development of a differential diagnosis, (2) clarity and continuity of documentation, and (3) psychosocial assessment of the family and fertility experience. All participants felt that the current nomenclature was not sufficient for their clinical practice and would support additional standard symbols. This study supports the need for development of further pedigree nomenclature inclusive of patients with ART experiences.

Professionally responsible management of the ethical and social challenges of antenatal screening and diagnosis of ß-thalassemia in a high-risk population.

Thalassemias are among the most frequent genetic disorders worldwide. They are an important social and economic strain in high-risk populations. The benefit of ß-thalassemia screening programs is growing evident but the capacity to diagnose fetal ß-thalassemia exceeds the treatment possibilities and even when treatment before birth becomes feasible, difficult decisions about the relative risks will remain. This paper can be of practical and ethically justified aid when counseling women about screening, diagnosis, and treatment of ß-thalassemia. It takes in consideration various social challenges, medical issues such as antenatal screening, preimplantation genetic diagnosis, prenatal diagnosis, non-invasive prenatal testing and prenatal therapy. We also describe the Sardinian experience in applying and promoting high-risk population screening and diagnosis programs and future trends in the management of ß-thalassemia.

Preimplantation genetic diagnosis for a carrier with m.3697G > A mitochondrial DNA mutation.

OBJECTIVE: To explore inheritance of the m.3697G > A mitochondrial DNA (mtDNA) mutation and the effectiveness of preimplantation genetic diagnosis (PGD) for the carrier. METHODS: The study encompassed a pedigree of m.3697G > A mtDNA mutation, including one asymptomatic patient who pursued for PGD treatment. Twelve cumulus oocyte complexes (COCs) were collected in the first PGD cycle and 11 COCs in the second cycle. The efficiency of cumulus cells, polar bodies, and trophectoderm (TE) in predicting the m.3697G > A heteroplasmy of embryos was analyzed. RESULTS: From 23 COCs, 20 oocytes were fertilized successfully. On day 5 and 6 post-fertilization, 15 blastocysts were biopsied. The m.3697G > A mutation load of TE biopsies ranged from 15.2 to 100%. In the first cycle, a blastocyst with mutation load of 31.7% and chromosomal mosaicism was transferred, but failed to yield a clinical pregnancy. In the second cycle, a euploid blastocyst with mutation load of 53.9% was transferred, which gave rise to a clinical pregnancy. However, the pregnancy was terminated due to fetal cleft lip and palate. The mutation loads of different tissues (47.7 ± 1.8%) from the induced fetus were comparable to that of the biopsied TE and amniotic fluid cell (49.7%). The mutation load of neither cumulus cells (R2 = 0.02, p = 0.58) nor polar bodies (R2 = 0.33, p = 0.13) correlated with TE mutation load which was regarded as a gold standard. CONCLUSIONS: The m.3697G > A mutation showed a random pattern of inheritance. PGD could be used to reduce the risk of inheritance of a high mutation load. Cumulus cells are not a suitable predictor of blastocyst mutation load.