[THE RISK FOR CLINICALLY SIGNIFICANT COPY NUMBER VARIANTS IN PREGNANCIES WITH TWO SOFT MARKERS].

INTRODUCTION: Soft sonographic markers, such as an intracardiac echogenic focus, are demonstrated in one out of 150 live births and are associated with a slightly increased risk of trisomy 21 and 18. In the case of an isolated soft marker, the recommendation to perform invasive tests such as amniocentesis or placental cyst testing depends to a large extent on the results of biochemical first and second trimester maternal serum screening. In the case of two soft markers, the women are referred to genetic counseling, and invasive testing is funded by the Ministry of Health. OBJECTIVES: To estimate the risk for clinically significant copy number variants (CNVs) in pregnancies with two soft markers. METHODS: This retrospective cohort study included all prenatal microarray tests performed during 2013-2021, due to demonstration of two soft markers (namely: echogenic intracardiac foci, choroid plexus cyst, single umbilical artery and mild pyelectasis). The rates of clinically significant (pathogenic and likely pathogenic) microarray findings were compared to a previously published cohort of 7235 pregnancies with normal ultrasound, in which 87 (1.2%) abnormal CNVs were noted. RESULTS: Of the 150 pregnancies with two soft markers, two (1.3%) clinically significant CNVs were found. The rate of abnormal microarray findings did not differ from baseline risk in pregnancies with normal ultrasound - relative risk of 1.11 (95% confidence interval 0.28-4.40). CONCLUSIONS: The risk for abnormal microarray findings in pregnancies with two soft markers was not significantly increased in comparison to control group of pregnancies with normal sonography. DISCUSSION: These results undermine the current national policy of genetic counseling and Ministry of Health-funded invasive testing in pregnancies with a combination of two soft markers. These findings are important for additional countries with similar management, and may facilitate the genetic counseling and informed decision-making in such cases.

Compliance and satisfaction with BRCA surveillance in specialized clinics versus community follow-up.

OBJECTIVE: To assess adherence to medical follow-up protocols among BRCA1/2 carriers and compare outcomes between dedicated carrier clinics and community healthcare settings. METHODS: This cross-sectional study was conducted by distributing an anonymous questionnaire within the 'Good BRCA Genes - Support and Information Group for BRCA Carriers' association. The questionnaire assessed adherence to recommended surveillance and satisfaction with various aspects of the follow-up. RESULTS: Of the 682 BRCA carriers surveyed, 68.5% reported fully adhering to recommended medical follow-up. Those not fully adhering cited bureaucracy challenges, scheduling difficulties, timing uncertainties, and difficulty remembering examination dates. Less than 50% were satisfied with appointment availability, scheduling, contact persons, and general practitioners' knowledge of BRCA carrier risks and follow-up. The 417 women monitored in dedicated breast clinics reported notably higher optimal adherence to recommended surveillance (78.3 vs. 53.6%, P < 0.0001). In addition, they noted greater satisfaction with appointment availability (63.7 vs. 25.0%, P < 0.0001), appointment scheduling process (58.1 vs. 24.7%, P < 0.0001), availability of breast surgeons/gynecology specialists (67.4 vs. 50.8%, P < 0.0001), and availability of a contact person for consultations between appointments (53.5 vs. 20.8%, P < 0.0001). DISCUSSION: Our findings highlight the advantages of surveillance in dedicated BRCA1/2 clinics, including closer monitoring and increased satisfaction. Given the limited availability of such clinics and the growing number of BRCA1/2 carriers, the opening of additional dedicated clinics and the consideration of alternative surveillance-enhancing solutions, such as training healthcare professionals, using digital tools, and employing artificial intelligence, are essential.

Recommendations of Health Care Professionals on the Issue of Breastfeeding in BRCA Carriers.

Purpose: Breastfeeding is associated with numerous short- and long-term neonatal and maternal health benefits. Specifically, in BRCA1/2 female carriers, breastfeeding has been shown to reduce the considerably increased risks of breast and ovarian cancer. Nevertheless, there is paucity of data referring to the recommended postpartum surveillance of BRCA1/2 carriers. The purpose of this study was to evaluate the recommendations of health professionals regarding breastfeeding in BRCA carriers. Methods: This cross-sectional survey was conducted using an anonymous questionnaire distributed through the "Good BRCA Genes-a support and information group for BRCA carriers" association. The questionnaire included Likert scale and open-ended questions, aimed to evaluate the performance of health professionals at various aspects of the recommended follow-up. Results: Of the 388 participants, 233 (60.0%) expressed dissatisfaction with explanations provided by health professionals regarding pregnancy and breastfeeding. Women reporting dissatisfaction with explanations were younger (36.8 ± 7.0 years) compared to those satisfied with the explanations (38.8 ± 7.6 years, p = 0.0081). No significant differences were noted between women satisfied and those dissatisfied with the explanations in terms of age of genetic diagnosis, origin, religion, geographic location, and the rates of personal or familial cancer history. Of the 175 responses to an open question "please describe the reasons for unsatisfactory explanation," 76.6% stated they received no explanation on the subject, whereas 5.4% described minimal explanation or conflicting recommendations. Surprisingly, 4.7% recalled being advised to avoid, stop, or limit breastfeeding. Discussion: The results of this survey emphasize the lack of knowledge of health professionals on the issue of breastfeeding in BRCA carriers. As genetic variants in these genes involve significant proportion of the population (up to 2.5% in Ashkenazi Jewish population), raising the awareness of health care personnel to the benefits of breastfeeding in these women seems prudent.

National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.