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Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018–2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p

Objective To examine chromosomal microarray analysis results in pregnancies with various ultrasonographic anomalies and to characterize the copy number variants in diverse fetal phenotypes. Methods We retrospectively examined chromosomal microarray analyses of amniocenteses performed nationwide as a result of fetal ultrasonographic anomalies (structural defects, fetal growth restriction, and polyhydramnios) between January 2013 and September 2017. The rate of abnormal chromosomal microarray findings was compared between the different phenotypes and with a previously described control population of 15,225 pregnancies with normal ultrasonographic findings. Results Clinically significant chromosomal microarray aberrations were detected in 272 of 5,750 pregnancies (4.7%): 115 (2%) karyotype-detectable and 157 (2.7%) submicroscopic. Most commonly detected copy number variants were 22q11.21 deletions (0.4%) followed by 22q11.21 gain of copy number (0.2%). Specific copy number variants detected among pregnancies with abnormal ultrasonographic findings were up to 20-fold more prevalent compared with low-risk pregnancies. Some variants were associated with specific phenotypes (eg, 22q11.21 microdeletions with cardiovascular and 17q12 microdeletions with genitourinary defects). Conclusion The rate of abnormal amniotic chromosomal microarray analysis results is twice that of karyotypic abnormalities in pregnancies with various abnormal ultrasonographic findings.

Objectives To examine the risk for chromosomal aberrations in fetuses of colchicine-treated patients in a large cohort, and to perform a systematic literature review on the subject. Methods For the observational study, a retrospective search was performed through the Ministry of Health computerized database, for all invasive tests performed due to parental colchicine treatment over the years 2003–19. The rate of aberrant karyotypes in pregnancies exposed to colchicine was compared with a local cohort of 2752 normal pregnancies, yielding six (0.2%) karyotype-detectable findings. In addition, a systematic literature search was conducted for studies examining the rate of chromosomal aberrations in pregnancies exposed to colchicine. Results The study group consisted of 755 pregnancies karyotyped due to colchicine exposure. A marked decrease due to this indication was noted over the years (i.e. 67 cases in 2003 vs 8 in 2019). Five (0.66%) chromosomal aberrations were noted: 47,XXY; 45,X0; 47,XYY; and two fetuses with trisomy 21. This rate was significantly increased compared with the control population [relative risk 2.2 (95% CI: 1.1, 4.2)]. Literature search yielded four studies encompassing 740 pregnancies. The rate of chromosomal aberrations ranged from ‘none’ (in three studies) up to 1.5%. Quality assessment of the evidence was defined as ‘low’. Conclusion The results of our observational study support the concern that colchicine treatment is associated with increased risk for fetal chromosomal aberrations; however, the absolute risk is relatively low (one in 151 pregnancies). This information should be taken into account when considering invasive testing in such pregnancies.

Amniocentesis is an invasive procedure performed during pregnancy to determine, among other things, whether the fetus has Down syndrome. It is often preceded by screening, which gives a probabilistic risk assessment. Thus, ample information is conveyed to women with the goal to inform their decisions. This study examined the factors that predict amniocentesis uptake among pregnant women of advanced maternal age (older than 35 years old at the time of childbirth). Participants filled out a questionnaire regarding risk estimates, demographics, and attitudes on screening and pregnancy termination before their first genetic counseling appointment and were followed up to 24 weeks of gestation. Findings show that women's decisions are not always informed by screening results or having a medical indication. Psychological factors measured at the beginning of pregnancy: amniocentesis risk tolerance, pregnancy termination tolerance, and age risk perception affected amniocentesis uptake. Although most women thought that screening for Down syndrome risk would inform their decision, they later stated other reasons for screening, such as preparing for the possibility of a child with special needs. Findings suggest that women's decisions regarding amniocentesis are driven not only by medical factors, but also by a priori attitudes. The authors believe that these should be addressed in the dialogue on women's informed use of prenatal tests.

Background Risk for foetal Down syndrome (DS) increases as maternal age increases. Non-invasive screening (maternal serum triple test) for DS is routinely offered to pregnant women to provide risk estimates and suggest invasive amniocentesis for definitive pre-natal diagnosis to high-risk women. Objective We examined women's decision process with regard to pre-natal screening, and specifically, the degree to which they take into account triple serum screening results when considering whether or not to undergo amniocentesis. Design Semi-structured phone interviews were conducted to assess recall of DS screening results, understanding of risk estimates and their effect on women's decision whether to undergo amniocentesis. The study included 60 pregnant Israeli women (half younger than 35 and half advanced maternal age – AMA), with normal DS screening results and no known ultrasound abnormalities. Results Age appeared to determine the decision process. The vast majority of AMA women had amniocentesis, many of them before receiving their DS screening results. Most AMA participants knew that their risk estimate was ‘normal’, but still considered themselves at high risk due to their age. Procedure-related risk (miscarriage) and other factors only had a minor effect on their decision. A minority of younger women had amniocentesis. Younger women mentioned procedure-related risk and having normal screening results as the main factors affecting their decision not to have amniocentesis. Conclusion Age 35 is an anchor for the pre-determination regarding performing or avoiding amniocentesis. AMA women mention ‘age’ as their main reason to have amniocentesis and considered it an independent risk factor.

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.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.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.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.

Background A primary goal of amniocentesis is the detection of trisomy 21 (Down syndrome- DS) in the fetus. This procedure involves a small risk of miscarriage. As the risk of DS increases with maternal age, screening tests (maternal serum triple test and others) and age are used to generate a risk assessment, and amniocentesis is offered to women with high risk. In Israel, amniocentesis is government funded for women of advanced maternal age (AMA, i.e., ≥35 years), even if their risk assessment is low. The purpose of this study was to explore the reasons AMA women undergo amniocentesis, their knowledge about risk estimates, and to evaluate whether their decision is informed. Methods Shortly after undergoing amniocentesis, 42 consecutive women without a medical indication for amniocentesis other than age, completed a questionnaire that assessed their knowledge and opinions regarding screening tests, pregnancy termination, amniocentesis risks and the factors that affected their decision. Results Women rarely deliberated before undergoing amniocentesis. One third of those who had the screening test did not wait for the results before undergoing amniocentesis. Only one third of those who received the screening results remembered their risk estimation before going ahead with amniocentesis. Almost half (41 %) cited “age” as their main reason for undergoing amniocentesis, though only 44 % of these women could recall their age related DS risk. Sixty percent estimated their DS risk as low or very low but still had amniocentesis. Most participants (74 %) stated that they would consider termination of the pregnancy if the fetus was diagnosed with an intellectual deficit. Conclusions These results cast doubt on whether AMA women’s decision to undergo amniocentesis is based on risk estimates, as women seem to disregard risk estimates, and sometimes not even wait for them when making the decision. The policy of funding amniocentesis solely on the basis of age may have led to the conception that being over 35 alone is sufficient reason to undergo amniocentesis. This finding should inform policy makers, as it raises questions about the link between public funding and the choices of individual women, and has implications for healthcare expenditures.

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Moroccan Jewry (N>750,000) is the only non-Ashkenazi Jewish community in which Tay-Sachs disease (TSD) is not extremely rare. Previous studies among Moroccan Jewish TSD families identified three HEXA mutations. In this study, extended to enzyme-defined and new obilgate TSD carriers, we found four additional mutations. One of them is a novel, IVS5-2(A-->G) substitution, resulting in exon skipping, and it was found only among enzyme-defined carriers. The seven HEXA identified mutations among Moroccan Jews are: deltaF(304/305), R170Q, IVS-2(A-->G), Y180X, E482K, 1278+TATC, and IVS12+1(G-->C). Their respective distribution among 51 unrelated enzyme-defined and obligate carriers is 22:19:6:1:1:1:1. The mutation(s) remain unknown in only three enzyme-defined carriers. Five of the seven Moroccan mutations, including the three most common ones, were not found among Ashkenazi Jews. Compared with the much larger and relatively homogeneous Ashkenazi population, the finding among Moroccan Jews probably reflects their much longer history.

Aims: To evaluate the cross-trimester multiple marker correlation and the minimum marker combination needed for detecting various chromosomal aneuploidies. Materials and methods: Parturient women with singleton pregnancies who underwent non-interventional sequential screening test and followed prospectively were recruited. They all underwent first trimester combined nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A), and free β-human chorionic gonadotrophin (f-βhCG), followed by second trimester measurement of unconjugated estriol (uE 3 ), human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP). Pearson correlation was applied to compute any cross-trimester marker correlation and logistic regression analysis was used to determine the minimum marker combination for detecting various categories of chromosomal aneuploidies. Results: The current study included 552 normal and 43 chromosomal-affected pregnancies (24 Down's syndrome [DS], 7 Turner's syndrome, 8 Edward's syndrome, 4 Klinefelter syndrome and 5 triploidy) for which the results of both the screening tests and the pregnancy outcome were available. In the normal cases, a significant correlation was found between f-βhCG and hCG (r=0.52), as well as between PAPP-A and uE 3 (r=0.174). In DS pregnancies, the NT correlated with both hCG (r=0.45) and uE 3 (r= -0.39). In Turner's syndrome, uE 3 correlated both with PAPP-A (r=0.97) and f-βhCG (r=0.97). No other significant correlations were found. Furthermore, with the exception of f-βhCG and hCG in the unaffected cases, all other markers correlation appeared very weak. For detecting all the above categories of aneuploidies, the combination of NT, PAPP-A and uE 3 and the maternal age background risk were found adequate, with a 74% detection rate (DR) for a 5% false positive rate (FPR). For DS only, the combination of maternal age-related background risk and the combination of NT, PAPP-A, hCG and AFP yielded a 79% DR for a 5% FPR. Conclusions: The current study agrees with a previous report that, overall, there is no strong correlation between first and second trimester markers. The extension of the integrated test for detecting various categories of common chromosomal aneuploidies using NT, PAPP-A and uE 3 deserves further evaluation.

Objectives: To examine the assumption that amniotic fluid alpha-fetoprotein (AFAFP) levels are different in female and male twin fetuses. Design: Amniotic fluid levels of AFP in pregnancies with female and male fetuses in gender-concordant and gender-discordant twins were compared. A t test of p < 0.05 was considered significant. Material and Methods: Between 1995 and 1999, 332 genetic amniocenteses on twin pregnancies were performed at Meir Hospital, Kfar Saba, and Rambam Hospital, Haifa, Israel. One hundred and sixty-six were concordant for gender (84 females and 82 males) while 166 pairs differed in their gender. The amniotic fluid AFP levels of each sac were measured using fluorescent immunoassay methods by an AutoDELFIA machine. Results: The mean levels of AFAFP were lower in female twins compared to their male counterparts in same-gender twins (p = 0.07), although the difference was quite small. Nevertheless, there was no such difference between AFAFP of male versus female fetuses in gender-discordant twins. Conclusions: The levels of AFAFP were higher in the male twins of gender-concordant twins in comparison to female twins. No such difference was found between female versus male fetuses in gender-disconcordant twins.