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TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers., (© 2024. The Author(s).)

Background: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied., Methods: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance., Results: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001)., Conclusion: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests., (© 2024 John Wiley & Sons Ltd.)

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020-January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.

Background: Chromosomal microarray analysis (CMA) may detect variants of uncertain clinical significance (VUS) and susceptibility loci (SL) with incomplete penetrance for neurodevelopmental disorders. This qualitative study provides empirical data on women's experiences with receiving such findings in pregnancy and their decisions regarding continuation or termination of the pregnancy., Methods: Semi-structured interviews were conducted with women who received a VUS and/or SL from prenatal CMA in the last 2-4 years and were analyzed using Grounded Theory., Results: The vast majority of women recalled being stressed by the findings. All women sought further advice and information to be able to decide whether to continue or terminate their pregnancy. The three pregnancies that were terminated have in common a de novo SL with a 10%-20% penetrance. Similar reasoning (coping with uncertainty, the quest for a perfect child, and a chance for recurrence in future pregnancies) led different women to contradicting conclusions regarding their pregnancies. All women felt satisfied with their decisions., Conclusion: Although uncertain/probabilistic information commonly involves a psychological burden, it may also be perceived as valuable and actionable. Pre-test parental choice regarding the disclosure of such information could allow personalized utilization of advanced genomic tests in pregnancy., (© 2023 John Wiley & Sons Ltd.)

Background: Copy number variants (CNVs) associated with late-onset medical conditions are rare but important secondary findings in chromosomal microarray analysis (CMA) performed during pregnancy. Here, we critically review the cases at two tertiary centres to assess the criteria which guide the disclosure of such findings and develop a disclosure decision tool (DDT) aimed at facilitating disclosure decision. Parental decisions on receiving CNVs associated with risks for late-onset conditions were also recorded., Methods: Prenatal CMAs in Hadassah and Shaare Zedek Medical Centers from November 2013 to October 2021 were reviewed for CNVs associated with late-onset conditions. The DDT proposed uses a five-parameter scoring system, which considers the severity, median age of onset, penetrance, understanding of genotype-phenotype correlation and actionability of the finding., Results: Out of 16 238 prenatal CMAs, 16 (0.1%) harboured CNVs associated with late-onset conditions, 15 of which were disclosed. Outcome information was available on 13 of the 16 pregnancies, all of which continued to delivery., Conclusions: Our suggested DDT will help clinicians to quantitatively weigh the variables associated with CNVs of this type and arrive at a well thought out clinical decision regarding disclosure. Although the prevalence of late-onset conditions as a major finding in the prenatal setup is low, it is expected to rise with the increasing use of non-invasive CMA testing and whole exome and genome sequencing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Genetic variants of uncertain significance (VUSs) pose a growing challenge for patient communication and care in precision genomic medicine. To better understand patient perspectives of VUSs, we draw on qualitative analysis of semi-structured interviews with 22 cancer patients and individuals with cancer family history who received a VUS result. The majority of patients did not recall receiving VUS results and those who remembered expressed few worries, while respondents who were tested because of a family history of cancer were more concerned about the VUS results. Personal characteristics, medical condition, family history, expectations prior to testing, and motivations for pursuing testing influence the ways patients came to terms with the uncertainty of the VUS result. We conclude by discussing the relevance of the findings to the debate on the responsibility of the patient in checking back for VUS reclassification and to implications for genetic counseling that emphasizes tailoring the pre- and post-test discussion of VUS as appropriate to the patients' informational as well as emotional needs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

While genomic medicine is becoming an important part of patient care with an ever-increasing diagnostic yield, communicating variants of uncertain clinical significance (VUSs) remains a major challenge. We draw on qualitative analysis of semi-structured interviews conducted in 2020 with 20 Israeli healthcare professionals and stakeholders involved in communicating the results of genome-wide sequencing to patients. Respondents described four main strategies of communicating VUSs to patients: preparing the patient pre-test for uncertainty; adapting the level of detail to the patient's needs; upgrading versus downgrading the VUS; and following up on the possible reclassification of VUSs. These strategies were expressed differently by physicians and genetic counselors, varying according to their specialty and perception of the patient's situation. We discuss the strategic management and communication of uncertain genomic test results with patients in the context of meeting patients' expectations and working toward genetic causality through genomic narration and designation., (© 2022 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied., Methods: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions., Results: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support., Conclusion: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

While genomic medicine is becoming an important part of patient care with an ever-increasing diagnostic yield, recontacting patients after reclassification of variants of uncertain clinical significance (VUSs) remains a major challenge. Although periodical reinterpretation of VUSs is highly desired, recontacting former patients with new classifications is commonly not fulfilled in practice. We draw on semi-structured interviews with 20 Israeli healthcare professionals and stakeholders involved in communicating the results of genome-wide sequencing to patients. Findings show agreement that an individual health care professional cannot address the task of recontacting patients after re-classification, and that responsibility should be shared among the medical specialties, laboratory scientists, as well as patients. In the absence of established guidelines, many respondents suggested that the patient should be informed about reclassification during a follow-up contact but they disagreed who should be responsible for informing the patient. HCPs agreed that the solution to this challenge involves a centralized automated database that is accessible, continuously updated, and facilitates retrospective as well as prospective flagging of reclassification for patients who can benefit from this information. National and international policies providing concrete guidelines on the optimal way to recontact patients with new valuable genomic information are needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings., Methods: Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3)., Results: Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage., Conclusion: HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views., (© 2021 John Wiley & Sons Ltd.)

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1-TPDS) associated with an increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family-specific inactivating variants. We identified seven families, six of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a "likely pathogenic" status. Given a nonclassical BAP1-TPDS tumor type clustering and low penetrance in these families, the pathogenicity of this variant was re-evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on the transcript, and tumor protein expression patterns. None of the three available tumors showed an allelic loss, there was no discernable effect on alternative splicing based on reverse-transcription polymerase chain reaction, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be reclassified as a variant of unknown significance by American College of Medical Genetics (ACMG) criteria., (© 2021 Wiley Periodicals LLC.)

Objectives: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings., Methods: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group., Results: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed., Conclusion: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Purpose of Review: Chromosomal-microarray analysis (CMA) is the first-tier test in pregnancies with structural malformations. Accumulating data show that pathogenic copy number variants (CNVs) can also be identified in structurally normal fetuses. We set out to summarize the published data on the diagnostic yield of CMA in structurally normal fetuses., Recent Findings: Six studies summarize a total of 29,612 prenatal CMAs performed in structurally normal fetuses. The incidence of highly penetrant pathogenic/likely pathogenic CNVs is 0.4-2.5%. Variability was demonstrated in the timing of CMA testing and type of CNVs classified as pathogenic. The incidence of variants of uncertain significance is 0.4-5.4%. The prevalence of susceptibility loci is 0.3-0.7% when specified, and the incidence of CNVs associated with late onset disease is 0.1%., Summary: With a frequency of abnormal CNVs of 1:40 to 1:250 in structurally normal fetuses, it is recommended that all pregnant women be informed of the possibility to have CMA performed, even in the absence of malformations. Information should also be provided about uncertain and secondary findings., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe the WFS1 c.1672C>T; p.R558C missense variant, found in 1.34% of Ashkenazi Jews, that has a relatively mild phenotype and to use computational normal mode analysis (NMA) to explain the genotype-phenotype relationship., Methods: The clinical, laboratory, and genetic features of 8 homozygotes were collected. A model of the wolframin protein was constructed, and NMA was used to simulate the effect of the variant on protein thermodynamics., Results: Mean age at Wolfram syndrome (WS) diagnosis among homozygotes was 30 years; diabetes (7/8) was diagnosed at mean age 19 years (15-21 years), and bilateral optic atrophy (with MRI evidence of optic/chiasm atrophy) (6/8) at mean age 29 years (15-48 years). The oldest patient (62 years) also had gait difficulties, memory problems, parietal and cerebellar atrophy, and white matter hyperintense lesions. All retained functional vision with independent ambulation and self-care; none had diabetes insipidus or hearing loss. The p.R558C variant caused less impairment of protein entropy than WFS1 variants associated with a more severe phenotype., Conclusions: The p.R558C variant causes a milder, late-onset phenotype of WS. We report a structural model of wolframin protein based on empirical functional studies and use NMA modeling to show a genotype-phenotype correlation across all homozygotes. Clinicians should be alert to this condition in patients with juvenile diabetes and patients of any age with a combination of diabetes and optic atrophy. Computational NMA has potential benefit for prediction of the genotype-phenotype relationship., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Prenatal genetic testing and analysis in the past was usually only offered when a particular fetal phenotype was noted or suspected, meaning that filtering and interpretation of genetic variants identified could be anchored in attempts to explain an existing health concern. Advanced genomic testing is now increasingly used in "low-risk" pregnancies, producing information on genotype adrift of the phenotypic data that is necessary to give it meaning, thus increasing the difficulty in predicting whether and how particular genetic variants might affect future development and health. A challenge to healthcare scientists, clinicians, and parents therefore is deciding what qualities prenatal genotypic variation should have in order to be constructed as a 'result.' At the same time, such tests are often re requested in order to make binary decisions about whether to continue a pregnancy or not. As a range of professional organizations develop guidelines on the use of advanced genomic testing during pregnancy, we highlight the particular difficulties of discovering ambiguous findings such as variants with uncertain clinical significance, susceptibility loci for neurodevelopmental problems and susceptibility to adult-onset diseases. We aim to foster international discussions about how decisions around disclosure are made and how uncertainty is communicated.

Background: Chromosomal-microarray-analysis (CMA) can identify variants of uncertain clinical significance, susceptibility-loci for neurodevelopmental conditions, and risk for adult-onset conditions. We explored choices made by couples undergoing prenatal CMA, their understanding of these findings, reasons for and against receiving them, and whether they believe parents or professionals should decide which are disclosed., Methods: Semi-structured interviews were conducted with women (n = 27) or their partners (n = 15) during the week following prenatal CMA testing and analyzed using grounded theory., Results: Over half the interviewees (55%) recalled at least two of the three types of CMA results they chose whether to receive. Sixty-four percent found the choice simple, whereas 36% found it difficult. All participants could clearly explain their choices, which were based on the perceived actionability and psychological impact of the information. Sixty percent viewed their choice favorably, whereas ~21% would have preferred clinicians to decide for them. More women than men, and more decisive than indecisive participants supported parental choice., Conclusion: Overall, expectant parents can make informed choices about which uncertain findings about their fetuses they wish to receive, and value the opportunity to tailor results to their values and wishes. Arguments presented provide the basis for a decision-aid tool for expecting parents., (© 2020 John Wiley & Sons Ltd.)

Objective: To examine the choices of women with both high-risk and low-risk pregnancies who are undergoing prenatal chromosomal microarray analysis in a clinical setting regarding three challenging types of findings: variants of uncertain clinical significance, susceptibility loci for neurodevelopmental disorders, and copy number variants associated with risks for adult-onset conditions. We assessed whether women's choices were associated with indications for testing or with one-on-one pretest genetic counseling., Methods: In this cross-sectional study, medical records of women who underwent invasive prenatal chromosomal microarray analysis testing (N=1,070) at Hadassah Medical Center between June 2017 and February 2018 were examined for testing indications, choices regarding chromosomal microarray analysis findings, and type of pretest genetic counseling. Multivariable analyses to assess associations with testing indication and prior genetic counseling were carried out using logistic regression models., Results: In total, 56% of women (n=593) chose to be informed of all three types of findings and 20% (n=218) chose not to be informed of any of the findings beyond high-penetrance childhood-onset pathogenic findings. Variants of uncertain clinical significance as a single choice was the least-selected finding (2.5%, n=27). Low-risk pregnancies (ie, those with normal biochemical screening and fetal ultrasound examinations) were associated with increased interest in receiving genetic information about adult-onset conditions (adjusted odds ratio [aOR] 1.7; 95% CI 1.18-2.33) and susceptibility loci (aOR 1.5; 95% CI 1.08-2.10)., Conclusion: Women with both high-risk and low-risk pregnancies were generally more likely to choose to receive additional genetic information, albeit differences in preferences depend on testing indication and type of pretest counseling.

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward., (© 2019 Wiley Periodicals, Inc.)

Objective: Traditionally, amniocentesis is performed between 17 and 23 weeks of gestation. This enables decisions regarding the course of pregnancy to be made before viability. Less frequently, amniocentesis is performed in the third trimester. Advanced genomic technologies such as chromosomal microarray analysis (CMA) provide more detailed information about the fetus compared with traditional G-banded chromosomal analysis. The aim of this study was to assess the indications for and safety of late amniocentesis, genetic-test results (especially in the context of CMA technology) and outcome of pregnancies that underwent the procedure after 24 weeks., Methods: Medical records were analyzed retrospectively of all women in whom amniocentesis was performed at a gestational age of 24 + 0 to 38 + 6 weeks, at Hadassah Medical Center, between June 2013 and March 2017. Parameters investigated included indications for late amniocentesis, complications, CMA results and pregnancy outcome., Results: During the study period, 291 women (303 fetuses, 277 singleton and 14 twin pregnancies; in two twin pairs, one fetus was terminated before amniocentesis) underwent late amniocentesis. CMA was performed in all instances of amniocentesis. The most frequent indication was abnormal sonographic finding(s) (204/303 fetuses, 67%). Preterm delivery occurred in 1.7% and 5.1% of pregnancies within the first week and within 1 month following the procedure, respectively. Aneuploidy was detected in nine (3%) fetuses and nine (3%) others had a pathogenic/likely pathogenic copy number variant, suggesting that CMA doubled the diagnostic yield of traditional karyotyping. Maximal diagnostic yield (17.5%) was achieved for the subgroup of fetuses referred with abnormal sonographic findings in two or more fetal anatomical systems. Variants of uncertain significance or susceptibility loci were found in another nine (3%) fetuses., Conclusions: In pregnancies undergoing late amniocentesis, CMA increased detection rates of fetal abnormalities and had a shorter turnaround time compared with traditional chromosomal analysis; therefore, late amniocentesis may serve as a helpful tool for detecting fetal abnormalities or reassuring parents following late-appearing abnormal sonographic findings. However, CMA may expose findings of uncertain significance, about which the couple should be precounseled. The procedure appears to be safe. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

Advanced genomic tests in pregnancy, such as chromosomal microarray analysis (CMA), provide higher detection rates yet often produce probabilistic and uncertain information. This study aimed to understand how the most knowledgeable patients, i.e., pregnant genetic counselors, act in their own pregnancies, thereby gaining insight into the impact of patients' knowledge on the diagnostic process. Seventeen interviews were conducted with Israeli genetic counselors, either pregnant or up to 2 years post-pregnancy. A third of the participants chose not to have CMA while two thirds underwent it despite no detected abnormalities. Although knowledge was the main motivation, counselors varied in the desired degree of information. Two thirds of those opting for CMA wished to have all findings identified whereas roughly one third asked for a targeted platform seeking to avoid uncertain results. Counselors were not quick to adopt new tests such as whole-exome sequencing. Being knowledgeable was described as promoting a sense of control yet also being a source of stress and moral dilemmas. While the basic premise of informed consent is crucial, it does not always make things easier for educated patients. Consequently, raising levels of patient knowledge is only a limited step forward in the search for best practice.

Purpose: The extent of the responsibility of health-care professionals (HCPs) to ensure that patients' relatives are told of their risk is unclear. Current international guidelines take confidentiality to the individual patient as the default position, but some suggest that disclosure could be default and genetic information could be conceptualized as familial., Methods: Our systematic review and synthesis of 17 studies explored the attitudes of HCPs, patients, and the public regarding the extent of HCPs' responsibility to relatives with respect to disclosure., Results: Health-care professionals generally felt a responsibility to patients' relatives but perceived a variety of reasons why it would be difficult to act on this responsibility. Public/patient views were more wide-ranging. Participants identified several competing and overlapping arguments for and against HCP disclosure: guidelines do not permit/mandate it, privacy, medical benefit, impact on family dynamics, quality of communication, and respecting autonomy., Conclusion: We argue that HCPs can sometimes share genetic information without breaching confidentiality and that they could factor into their considerations the potential harm to family dynamics of nondisclosure. However, we need more nuanced research about their responsibilities to relatives, particularly as genomic tests are used more frequently in clinical practice.Genet Med 18 4, 290-301.

Objectives: This study explored the views of healthcare professionals (HCPs) in the UK about what information should be disclosed, when; and whether women/parents should be given a choice as to what they wish to know., Methods: Q-methodology was used to assess the views of 40 HCPs (genetic HCPs, fetal medicine experts, lab-scientists)., Results: Most participants agreed that variants of unknown clinical significance should not be disclosed. Participants were divided between those who considered variants of uncertain clinical significance helpful for parents and clinicians, and those who considered them harmful. Although recognising the potential disadvantages of disclosing risks for adult-onset conditions, participants thought it would be difficult to withhold such information once identified. Participants largely supported some parental involvement in determining which results should be returned. Most participants believed that information obtained via CMA testing in pregnancy should either be disclosed during pregnancy, or not at all., Conclusion: HCPs taking part in the study largely believed that variants that will inform the management of the pregnancy, or are relevant to other family members, should be reported. Recent UK guidelines, published after this research was completed, reflect these opinions., (© 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.)

This study set out to explore the attitudes of a representative sample of the British public towards genetic testing in children to predict disease in the future. We sought opinions about genetic testing for adult-onset conditions for which no prevention/treatment is available during childhood, and about genetic 'carrier' status to assess future reproductive risks. The study also examined participants' level of agreement with the reasons professional organisations give in favour of deferring such testing. Participants (n=2998) completed a specially designed questionnaire, distributed by email. Nearly half of the sample (47%) agreed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. This runs contrary to professional guidance about genetic testing in children. Testing for carrier status was supported by a larger proportion (60%). A child's future ability to decide for her/himself if and when to be tested was the least supported argument in favour of deferring testing.

The rapidly declining costs and increasing speeds of whole-genome analysis mean that genetic testing is undergoing a shift from targeted approaches to broader ones that look at the entire genome. As whole-genome technologies gain widespread use, questions about the management of so-called incidental findings-those unrelated to the question being asked-need urgent consideration. In this review, we bring together current understanding and arguments about (1) appropriate terminology, (2) the determination of clinical utility and when to disclose incidental findings, (3) the differences in management and disclosure in clinical, research and commercial contexts and (4) ethical and practical issues about familial implications and recontacting those tested. We recommend that greater international consensus is developed around the disclosure and management of incidental findings, with particular attention to when, and how, less clear-cut results should be communicated. We suggest that there is no single term that captures all the issues around these kinds of findings and that different terms may, therefore, need to be used in different settings. We also encourage the use of clear consent processes, but suggest that the absence of consent should not always preclude disclosure. Finally, we recommend further research to identify ways to implement the use of a genome output as a resource, accessible over time, to facilitate appropriate disclosure and recontact when the significance of a previously unclear incidental finding is clarified., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: Advances in genomics may eventually lead to genetic susceptibility screening of the general population, regardless of a personal or familial history of the disease in question. Yet, little is known about clinicians' attitudes toward such programs. We explored attitudes of family practitioners, medical geneticists and genetic counselors toward genetic screening of the general Ashkenazi-Jewish population for the common founder mutations in BRCA1/2 and LRRK2 genes (which increase the risk of hereditary breast/ovarian cancers and Parkinson's disease, respectively)., Methods: Participants (n = 204) completed a specially designed questionnaire, distributed by e-mail, regular mail or in-person., Results: Slightly more than half (52%) were in favor of BRCA screening, while the vast majority (86%) opposed to LRRK2 screening. About two-thirds (68%) of the respondents supported pre-test genetic counseling. Attitudes were largely independent of professional background and sociodemographic characteristics, though a correlation was found with personal interest in genetic self-testing for the above genes. Adverse psychological impact and discrimination in insurance and employment were the major concerns cited by respondents with regard to screening programs., Conclusion: Our findings suggest that the availability of measures for prevention and/or treatment is a major factor in the attitudes of healthcare providers toward population screening for late-onset conditions., (Copyright © 2013 S. Karger AG, Basel.)

Purpose: BRCA genes are associated with hereditary breast and ovarian cancers. Guidelines worldwide currently recommend BRCA genetic testing in asymptomatic individuals only if they belong to "high-risk" families. However, population screening for BRCA1/2 may be the logical next step in populations with a high prevalence of founder mutations, such as Ashkenazi Jews. This study aimed to explore (i) the impact of a positive BRCA genetic test result on individuals who have neither a personal history nor a familial history of cancer and (ii) their attitudes toward the concept of population screening., Methods: Semistructured in-depth interviews were carried out with 14 Ashkenazi Jewish women who were asymptomatic BRCA carriers and who belonged to families with low prevalence of cancer., Results: Three main findings emerged: (i) having no family history of cancer was a source of optimism but also confusion; (ii) engaging in intensified medical surveillance and undergoing preventive procedures was perceived as health-promoting but also tended to induce a sense of physical and psychological vulnerability; and (iii) there was overall support for BRCA population screening, with some reservations., Conclusion: Women belonging to low-cancer-prevalence families within a "high-risk" ethnic community view BRCA genetic testing positively despite the difficulties entailed, because it allows prevention or early detection of cancer. However, implementing a BRCA population screening program should be carried out with proper pre- and post-testing preparation and support for the individuals undergoing testing.

Recently, the Israel National Bioethics Council (INBC) issued recommendations permitting egg freezing to prevent both disease- and age-related fertility decline. The INBC report forms the basis of Israel's new policy, being one of the first countries to regulate and authorise egg freezing for what it considers to be non-medical (ie, social) uses. The ethical discussion in the INBC report is reviewed and compared with the scant ethical discourse in the academic literature on egg freezing as a means of preventing age-related loss of fertility. We argue that both the INBC recommendations and the bioethical academic discourse on egg freezing are grounded in liberal ideology, which views technology as primarily enabling. Accordingly, they promote 'individual autonomy' as exercised through informed consent. Our study suggests that a relational approach to autonomy may be a more suitable model for considering women's choices about egg freezing.

Background: As in many advanced societies, the age at first birth and the rate of post-menopausal pregnancies in Israel are constantly increasing. Since Israeli university students are the most likely population to postpone parenthood, this study aims at evaluating their awareness of: (i) women's age-related fertility decline; (ii) age-dependent success rates of IVF technology and (iii) medical procedures allowing late and post-menopausal pregnancies., Methods: Israeli undergraduate students (n= 410), attending four academic institutions and studying in different fields, completed a structured questionnaire in the 2009/2010 academic year., Results: Students overestimated women's chances of spontaneous pregnancy in all age groups, whereas women's chances of achieving a live birth following IVF treatment were overestimated only for ages 40 years and above. Regarding both spontaneous and IVF pregnancies, success rates of very late pregnancies (beyond 45 years and after menopause) were greatly overestimated. Only 11% of the students knew that genetic motherhood is unlikely to be achieved from the mid-40s onward, unless using oocytes frozen in advance., Conclusions: The findings demonstrate entrenched fertility myths among Israeli students, particularly the false belief in the possibility of late (beyond 35 years) and very late genetic motherhood. This can be explained by technological 'hype' and favorable media coverage of very late pregnancies. Since this may culminate in involuntary childlessness, it is highly important to increase the awareness of the Israeli public on the subject of fertility. However, as our sample is not representative of the Israeli student population, our findings should be tested in future studies.

In December 2009, the Israel National Bioethics Council (INBC) issued recommendations permitting egg freezing to prevent both disease- and age-related fertility decline. The INBC report forms the basis of Israel's new policy regarding egg freezing. This article analyzes the medical section of the INBC's recommendations, comparing it with guidelines formulated by medical regulatory bodies in Europe and the United States. Our findings suggest that the INBC's recommendations consider age-related fertility decline to be a medical problem, and hence treat the new technology favorably, as preventive medicine, which we perceive as another instance of medicalization. The technology's risks are downplayed by the INBC, unlike the positions of medical organizations in both Europe and the United States, which consider the new technology experimental. This may culminate in raising false hopes about women's possible late genetic motherhood leading to involuntary future childlessness., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)