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Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c. 109C>T (p. R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha-thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms. [ABSTRACT FROM AUTHOR]

Objective: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors., Method: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT., Results: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise)., Conclusion: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519&#95;1523del. Chromosomal breakage was significantly increased in patient cells, both spontaneously, and following mitomycin C exposure. Transfection of DYK-tagged FIGNL1 constructs in HEK293 cells showed no detectable protein in FIGNL1c.189del and truncation with reduced expression in FIGNL1c.1519&#95;1523del (64% of wild-type [WT], P = .003). FIGNL1 forms nuclear foci increased by phleomycin treatment (20.6 ± 1.6 vs 14.8 ± 2.4, P = .02). However, mutant constructs showed reduced DYK-FIGNL1 foci formation in non-treated cells (0.8 ± 0.9 and 5.6 ± 1.5 vs 14.8 ± 2.4 in DYK-FIGNL1WT, P < .001) and no increase with phleomycin treatment. In conclusion, FIGNL1 loss of function is a newly characterized OD gene, highlighting the DDR pathway's role in ovarian development and maintenance and suggesting chromosomal breakage as an assessment tool in XX-DSD patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To evaluate the rates of vaginal birth after cesarean (VBAC) among parturients attempting preterm trial of labor following a cesarean delivery (TOLAC) vs. term TOLAC., Methods: A multicenter historic cohort study was conducted at two university-affiliated centers between August 2005 and March 2021. Parturients in their second delivery, attempting TOLAC after a single low segment transverse cesarean delivery were included. We retrospectively examined computerized medical records of all preterm (< 37 weeks) and term (37-42 weeks) births. Multifetal gestations and postterm deliveries (≥ 42 weeks) were excluded. A univariate analysis was conducted, followed by a multivariate analysis., Results: 4865 second deliveries following previous cesarean were identified: 212 (4.4%) preterm and 4653 (95.6%) term. Hypertensive disorders, diabetes and fertility treatments were significantly more prevalent in the preterm group. VBAC rate was significantly lower in preterm group (57.5 vs 79.7%., p < 0.01), including both spontaneous and vaginal-assisted deliveries. In multivariate analysis, preterm TOLAC was independently associated with TOLAC failure [adjusted odds ratio 2.24, [95% confidence interval 1.62-3.09]. Overall, maternal outcomes were favorable. Rates of uterine rupture, re-laparotomy and postpartum hemorrhage were comparable between groups. Neonatal outcomes were less favorable among the preterm group; however, preterm vs. term TOLAC was not associated with low 5 min Apgar score (aOR 1.76, 95% CI 0.92-3.40)., Conclusion: In our study, VBAC rates were lower in preterm compared to term deliveries. Maternal outcomes were comparable. Neonatal outcomes were less favorable in the preterm group, more likely due to prematurity than delivery mode., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Hereditary breast and ovarian cancer (HBOC) is predominantly accounted for by pathogenic variants (PVs) in BRCA1/BRCA2 genes. Population screening for recurring PVs in Ashkenazi Jews (AJ) was incorporated into the Israeli health basket in 2020, increasing the identification of BRCA carriers. Information on cancer risks for each PV in Israel is limited., Aims: To assess genotype phenotype correlations of recurring BRCA PVs in Israeli carriers., Methods: A retrospective cohort of 3,478 BRCA carriers followed-up in 12 medical centers, comprising the HBOC Consortium, formed the basis of the study. Data were collected using the electronic database, and analyzed by Chi square, t-tests and Kaplan-Meier survival analysis., Results: Overall, 2145 BRCA1, 1131 BRCA2, and 22 double heterozygote PV carriers were analyzed. BRCA1 carriers had more cases of cancer (53.1% vs. 44.8%, p<0.001), ovarian cancer (OC) (17.1% vs. 10.6%, p<0.001), younger age at breast cancer (BC) (45.4 ±11.6SD years vs. 49.1 ±11.1SD years, p<0.001) and OC diagnosis (52.8 ±10.1SD yrs. vs. 61±10.6SD yrs. p<0.001), and more family history of BC (64.5% vs. 59.0%, p<0.001) and OC (36.7% vs. 27.3%, p<0.001) compared with BRCA2 carriers. Carriers of BRCA15382insC had more BC and less OC than BRCA1185delAG: 46.4% vs. 38.6% and 12.9% vs. 17.6% (p<0.04), respectively., Conclusions: In our population, similar to others, BRCA1 carriers have higher cancer rates and earlier age at diagnosis compared with BRCA2 carriers. The two recurring BRCA1 PVs have different risks: 5382insC carriers had more BC; 185delAG carriers had more OC. Risk-reducing measures should be based on variant-specific cancer risk.

Background: Maternal CMV infection during pregnancy, either primary or non-primary, may be associated with fetal infection and long-term sequelae. While guidelines recommend against it, screening for CMV in pregnant women is a prevalent clinical practice in Israel. Our aim is to provide updated, local, clinically relevant, epidemiological information about CMV seroprevalence among women at childbearing age, the incidence of maternal CMV infection during pregnancy and the prevalence of congenital CMV (cCMV), as well as to provide information about the yield of CMV serology testing., Methods: We performed a descriptive, retrospective study of women at childbearing age who were members of Clalit Health Services in the district of Jerusalem and had at least one gestation during the study period (2013-2019). We utilized serial serology tests to determine CMV serostatus at baseline and at pre/periconception and identified temporal changes in CMV serostatus. We then conducted a sub-sample analysis integrating inpatient data on newborns of women who gave birth in a single large medical center. cCMV was defined as either positive urine CMV-PCR test in a sample collected during the first 3 weeks of life, neonatal diagnosis of cCMV in the medical records, or prescription of valganciclovir during the neonatal period., Results: The study population Included 45,634 women with 84,110 associated gestational events. Initial CMV serostatus was positive in 89% women, with variation across different ethno-socioeconomic subgroups. Based on consecutive serology tests, the detected incidence rate of CMV infection was 2/1000 women follow-up years, among initially seropositive women, and 80/1000 women follow-up years, among initially seronegative women. CMV infection in pregnancy was identified among 0.2% of women who were seropositive at pre/periconception and among 10% of women who were seronegative. In a subsample, which included 31,191 associated gestational events, we identified 54 newborns with cCMV (1.9/1000 live births). The prevalence of cCMV among newborns of women who were seropositive at pre/periconception was lower than among newborns of women who were seronegative (2.1 vs. 7.1/1000). Frequent serology tests among women who were seronegative at pre/periconception detected most primary CMV infections in pregnancy that resulted in cCMV (21/24). However, among women who were seropositive, serology tests prior to birth detected none of the non-primary infections that resulted in cCMV (0/30)., Conclusions: In this retrospective community-based study among women of childbearing age characterized by multiparity and high seroprevalence of CMV, we find that consecutive CMV serology testing enabled to detect most primary CMV infections in pregnancy that led to cCMV in newborns but failed to detect non-primary CMV infections in pregnancy. Conducting CMV serology tests among seropositive women, despite guidelines' recommendations, has no clinical value, while it is costly and introduces further uncertainties and distress. We thus recommend against routine CMV serology testing among women who were seropositive in a prior serology test. We recommend CMV serology testing prior to pregnancy only among women known to be seronegative or women whose serology status is unknown., (© 2023. The Author(s).)

One-third of cesarean deliveries (CDs) are repeat operations, of which the majority are low-order, second (CD2) and third (CD3). The study objectives were to identify risk factors for a complicated maternal CD among women undergoing a repeat low-order CD and to develop a predictive model for at-risk women. A retrospective longitudinal follow-up study was conducted in a single medical center, during 2005-2016. Women who underwent both CD2 and CD3 at the site were included. Those with placenta accreta or a caesarean hysterectomy were excluded. A composite complicated maternal CD was defined by either uterine rupture/dehiscence, blood transfusion, relaparotomy, admission to the intensive care unit or prolonged operative time >90th percentile. Data was analyzed comparing between CD2 to CD3, each woman served as her own control. Univariate analysis followed by a multivariate logistic regression modeling were performed with an OR of 95% CI defining significance. The study group comprised of 1,331 women. A complicated CD occurred in 159 (12%) vs. 226 (17%) of CD2 vs. CD3 respectively, (p<0.001). Women with a complicated CD2 were at higher risk for complications in CD3, aOR 2.3 (95% CI 1.5, 3.3). Sub-Saharan African origin and preterm delivery at CD3 were both risk factors for a complicated CD3, aOR 3.7 (95% CI 1.9, 7.3) and aOR 1.7 (95% CI 1.1, 2.7), respectively. The multivariate regression model included 1328 cases, was statistically significant, χ2(7) = 50.760, p <0.001, explained 6.3% of the variance of composite complicated maternal CD3 and correctly classified 82.9% of cases. Although a complicated CD2, Sub-Saharan African origin and preterm delivery are risk factors for maternal complications in CD3, it is hard to predict which specific women will experience complications. Sensitivity, specificity, positive and negative predictive value of a complicated CD2 for detecting complications in CD3 were 21%, 90%, 30% and 85% respectively., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Reichman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Obstetric anal sphincter injures (OASIS) have long-term implications on women's health. Administration of antibiotic prophylaxis and treatment following OASIS repair is controversial. We conducted a national survey to provide data about practice routines regarding antibiotic prophylaxis and treatment following OASIS repair in Israeli labor and delivery units., Methods: A national survey was performed among obstetricians and gynecologists from 24 university-affiliated delivery centers within the jurisdiction of the Israeli Ministry of Health during 2020. Representatives from each center completed the "Google form" electronic survey. For each questionnaire item, the most common answer was chosen to represent the center's answer., Results: The number of physicians who responded per center varied from 1 to 14 (median, 3.5). Preoperative and postoperative antibiotic treatment was given in 75% and 92% of the centers, respectively. While most centers (58.3%) recommend pelvic floor physical therapy on release, recommendations about functional radiologic tests vary. In all centers, there is a designated clinic for postpartum follow-up of OASIS. Most centers (83%) allow trial of vaginal delivery in the subsequent pregnancy, on an individual basis., Conclusion: Heterogeneity exists in managing OASIS in Israel, particularly regarding administration of antibiotics. Further studies are needed to examine the consequences of different management protocols., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier’s relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (−3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.

Complex chromosomal rearrangements (CCRs), a class of structural variants (SVs) involving more than two chromosome breaks, were classically thought to be extremely rare. As advanced technologies become more available, it has become apparent that CCRs are more common than formerly thought, and are a substantial cause of genetic disorders. We attempted a novel approach for solving the mechanism of challenging CCRs, which involve repetitive sequences, by precisely identifying sequence-level changes and their order. Chromosomal microarray (CMA) and FISH analyses were used for interpretation of SVs detected by whole exome sequencing (WES). Breakpoint junctions were analyzed by Nanopore sequencing, a novel long-read whole genome sequencing tool. A large deletion identified by WES, encompassing the FOXF1 enhancer, was the cause of alveolar capillary dysplasia and respiratory insufficiency, resulting in perinatal death. CMA analysis of the newborn's mother revealed two duplications encompassing the deleted region in the proband, raising our hypothesis that the deletion resulted from the mother's CCR. Breakpoint junctions of complex SVs were determined at the nucleotide level using Nanopore long-read sequencing. According to sequencing results of breakpoint junctions, the CCR in the newborn was considered the consequence of at least one double-strand break during meiosis, and reassembly of DNA fragments by intra-chromosomal homologous recombination. Our comprehensive approach, combining cytogenetics and long-read sequencing, enabled delineation of the exact breakpoints in a challenging CCR, and proposal of a mechanism in which it arises. We suggest applying our integrative approach combining technologies for deciphering future challenging CCRs, enabling risk assessment in families., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Loss of function (LoF) mutations in Optineurin can cause recessive amyotrophic lateral sclerosis (ALS) with some heterozygous LoF mutations associated with dominant ALS. The molecular mechanisms underlying the variable inheritance pattern associated with OPTN mutations have remained elusive. We identified that affected members of a consanguineous Middle Eastern ALS kindred possessed a novel homozygous p.S174X OPTN mutation. Analysis of these primary fibroblast lines from family members identified that the p.S174X mutation reduces OPTN mRNA expression in an allele-dependent fashion by nonsense mediated decay. Western blotting correlated a reduced expression in heterozygote carriers but a complete absence of OPTN protein in the homozygous carrier. This data suggests that the p.S174X truncation mutation causes recessive ALS through LoF. However, functional analysis detected a significant increase in mitophagy markers TOM20 and COXIV, and higher rates of mitochondrial respiration and ATP levels in heterozygous carriers only. This suggests that heterozygous LoF OPTN mutations may not be causative in a Mendelian manner but may potentially behave as contributory ALS risk factors., (Copyright © 2021. Published by Elsevier Inc.)

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

Introduction: BRCA1/BRCA2 mutation carriers often undergo risk-reducing salpingo-oophorectomy (RRSO) before natural menopause, raising the issue of hormonal replacement treatment (HRT) use. There is conflicting evidence on the effect of HRT on breast cancer (BC) risk, and there are limited data on risk based on age at exposure. In the general population, HRT users have an increased BC risk (hazard ratio = 1.34). We assessed the impact of short-term HRT use on BC risk among healthy BRCA1/2 mutation carriers, with emphasis on age at exposure to HRT., Methods: A retrospective cohort of 306 consecutive healthy BRCA1/2 mutation carriers who had undergone RRSO was followed up for a mean of 7.26 years. We compared BC incidence over time in carriers who received HRT with that in those who did not receive., Results: Thirty-six of the carriers were diagnosed with BC, 20 of 148 patients (13.5%) in the HRT group compared with 16 of 155 (10.3%) in the non-HRT group (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 0.7-2.7). In women who were aged 45 years or younger at RRSO, HRT did not affect BC rates. However, in those older than 45 years at RRSO, BC rates were significantly higher in HRT users than in non-users (OR = 3.43, p < 0.05, 95% CI = 1.2-9.8)., Conclusions: In BRCA1/BRCA2 carriers in this study, short-term post-RRSO HRT use was associated with a threefold risk of BC in carriers older than 45 years. These results suggest that risk may be related to time of exposure to HRT around the natural age of menopause, even among BRCA1/2 carriers. Further studies are needed for validation and to guide future recommendations., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: We evaluated the yield of chromosomal microarray analysis in pregnancies complicated with fetal growth restriction (FGR) according to specific clinical parameters., Methods: The study was based on national records from the Israeli Ministry of Health. Chromosomal microarray analyses of amniocenteses performed nationwide for the indication of FGR, from January 2016 to March 2018, were included. The CMA yield was compared to 2 cohorts that reported the background risk., Results: Of 174 tests performed for the indication of FGR, there were 11 cases with a pathogenic/likely pathogenic result (6.3%). The yield of CMA was significantly higher in cases with major structural findings (29.4 vs. 3.4%, p = 0.001), compared to isolated FGR but not for minor structural findings (6.1 vs. 3.4%, p = 0.5). The rate of chromosomal aberrations was significantly higher for all cases with FGR, when compared to the background risk of a cohort of normal pregnancies (odds ratio [OR] 4.7, 95% CI 2.5-9 and OR 6.09, 95% CI 3.2-11.4) but not for isolated cases or cases diagnosed after 24 weeks of pregnancy., Conclusions: Chromosomal microarray analysis should be performed for all pregnancies complicated with FGR diagnosed before 24 weeks and for cases with major structural anomalies., (© 2020 S. Karger AG, Basel.)

Purpose: To investigate the prevalence of pathogenic and likely-pathogenic variants detected by chromosomal microarray analysis (CMA), among pregnancies with fetal short long bones diagnosed by ultrasound., Methods: The study cohort was based on cases of chromosomal microarray analyses performed nationwide for the indication of short long bones., Results: CMA was performed in 66 cases of short long bones. There were 4 cases with a pathogenic/likely pathogenic result (6%). The rate of chromosomal abnormalities was significantly higher compared to the background risk for copy number variations (CNVs) in pregnancies with no sonographic anomalies (P < 0.001). The yield of CMA in our cohort was significantly higher for both isolated and non-isolated cases, for cases in which the lowest estimated bone length percentile was above the 3rd percentile (below 5th percentile), and for cases diagnosed with short long bones after 22 weeks but not for cases diagnosed after 24 weeks., Conclusion: The yield of CMA in cases with short long bones (both isolated and non-isolated) is significantly higher than the background risk for chromosomal anomalies in pregnancies with no sonographic anomalies. This suggests that CMA should be offered in pregnancies with a diagnosis of fetal short long bones.

Purpose: Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model., Methods: We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability., Results: During 2012-2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p < 0.001). Residents initially had higher scores than specialists (pre: 66.3 ± 17.3 vs. 58.7 ± 16.6, respectively, p = 0.002); both significantly improved, with specialists "catching up" (post: 79.1 ± 17.2 vs. 75.7 ± 15.9, nonsignificant (NS)); there was a similar trend between fellows and subspecialists (pre: 70 ± 18 vs. 59.4 ± 16.4, respectively, p = 0.007; post: 78.6 ± 16.4 vs. 73.2 ± 17.7, respectively, NS). Younger specialists (≤10 years residency) had significantly higher pre- and post scores. Absolute improvement in scores did not depend on medical specialties., Conclusion: Our program is effective in improving genomics literacy for clinicians, irrespective of career length or expertise, and could be a model for improving skills in practical genomics for all medical professionals.

The founder variant DHCR7:c.964-1G>C causing autosomal recessive Smith-Lemli-Opitz (SLOS) was introduced into the Israeli preconception carrier program for Ashkenazi Jews in 2017 because of the high carrier frequency in this population (2.3%). Other disease-causing variants in DHCR7 are relatively rare in Israeli population. Discrepancy between the carrier frequency and disease prevalence raises the question of the actual risks for affected offspring for couples detected by the screening program. We performed a literature review of all relevant publications regarding homozygous DHCR7:c.964-1G>C fetuses/patients. We also collected clinical data about couples identified in the national screening program, including reproductive history. Out of 32 homozygous fetuses, six died in utero, 11 pregnancies were terminated during second trimester, and 15 children were born. All died between first days of life till 3 months of age. Reproductive history of SLOS-at-risk couples showed that after correction for ascertainment bias, out of 61 pregnancies, there was an absence of affected fetuses/children and an excess of miscarriages even if assumed that all the homozygous fetuses were miscarried. Out of these, eight families were Israelis, they had a total of one sick child, 21 healthy children, and 21 miscarriages. Our observations support the previous knowledge that homozygosity for c.964-1G>C in DHCR7 leads to a severe phenotype or early miscarriage. An unexpected observation was the excess of early miscarriages. This phenomenon is unclear and awaits further studies.

Background: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved., Method: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count., Results: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer)., Conclusion: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers., (© 2018 American Cancer Society.)

Background: Repeat cesarean delivery (CD) accounts for approximately 15% of all annual deliveries in the US with an estimated 656,250 operations per year. We aimed to study whether prolonged operative time (OT; skin incision to closure) is a risk marker for post-operative maternal complications among women undergoing repeat CD., Methods: We conducted a cross-sectional retrospective study in a single tertiary center including all women who underwent repeat CD but excluding those with cesarean hysterectomy. Prolonged OT was defined as duration of CD longer than the 90th percentile duration on record for each specific surgeon in order to correct for technique differences between surgeons. Bi-variate analysis was used to study the association of prolonged OT with each one of the following maternal complications: post-operative blood transfusion, prolonged maternal hospitalization (defined as hospitalization duration longer than 1 week post-CD), infection necessitating antibiotics, re-laparotomy within 7 days post-CD, and re-admission within 42 days post-CD. A multivariate regression analysis was performed controlling for maternal age, ethnicity, parity, number of fetus, gestational age at delivery, trial of labor after cesarean, anesthesia, and number of previous CDs. The adjusted odd ratio was calculated for each complication independently and for a composite adverse maternal outcome defined as any one of the above., Results: A total of 6507 repeat CDs were included; prolonged OT was highly associated (P value < 0.000) with: post-operative blood transfusion (4.4% vs. 1.5%), prolonged hospitalization (8.4% vs. 4.0%), infection necessitating antibiotics (2% vs. 1%), and readmission (1.8% vs. 0.8%) when compared to control. The composite adverse maternal outcome was also associated with prolonged OT (20.2% vs. 11.2%, p < 0.000). These correlations remained statistically significant in the multivariate regression analysis when controlling for confounders., Conclusions: Among women undergoing repeat CD, prolonged OT (reflecting CD duration greater than 90th percentile for the specific surgeon) is a risk marker for post-operative maternal complications.

We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10-3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22-90) years and for ovarian cancer (n = 15) 54 (38-69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.

Background/aim: To determine whether there are specific characteristic intrapartum heart rate patterns for fetuses with trisomy 21(T21)., Background Study Design/patients: Intrapartum fetal heart rate (FHR) tracings of T21 fetuses were compared to those of euploid fetuses in a retrospective, observational, matched, case-control study. The study group consisted of 42 fetuses with T21 and 42 matched euploid controls. Matching was designed to accommodate possible confounders. The sign test and McNemar's test were used for categorical variables. The paired t test was used for comparison between quantitative variables., Results: Intrapartum baseline FHR of fetuses with T21 was found to be slightly decreased compared to controls (122.5 vs 129.05 beats per minute, p=0.028). No differences were detected in the presence of periodic changes, or FHR variability between the groups., Conclusion: When evaluating intrapartum FHR of fetuses with T21, decreased baseline FHR can be expected., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Controversy exists about the impact of BRCA1/2 mutations on female fertility. Previous studies are small or based on indirect parameters (eg, self-reported infertility), which depend on additional factors unrelated to true fertility potential. Most of the previous studies did not use strict fertility markers., Objective: The aim of this study is to evaluate the relation between carrying a BRCA1/2 mutation and fertility using the level of anti-müllerian hormone (AMH), which has been previously shown to be an accurate marker of ovarian reserve and fertility potential., Patients and Methods: Forty-one healthy BRCA1/2 mutation carriers, aged 26 to 40 years, attending a multidisciplinary breast and ovarian cancer surveillance clinic, were tested for AMH levels using a 2-site ELISA. Levels were compared with those of our general population and with well-established normograms of the general population., Results: The mean age of carriers was 33.2 years (26-39 years; SD, 3.99 years). The mean parity of carriers was 1.97 (0-7; SD, 1.49). All women carried at least 1 Ashkenazi Jewish founder mutation. The AMH levels for most carriers were in the reference range, 2.71 ± 0.59 ng/mL (approximately 50th percentile of normograms). These levels were similar to those in the control group, in which the AMH levels were 2.02 ± 0.12 ng/mL (P = 0.27)., Conclusions: The AMH levels of healthy BRCA1/2 mutation carriers are similar to those of noncarrier women matched for age; therefore, their ovarian reserve is comparable. This is the only study, to the best of our knowledge, that directly examines ovarian reserve in a relatively large group of carriers with an accurate marker. The results of this study may possibly give reassurance to female carriers concerning fertility potential.

Molar tooth sign (MTS) is pathognomonic for Joubert syndrome (JS) and related disorders. We report a case in which MTS was suspected in an 'at risk' patient at 16 weeks' gestation by sonography and at 18 weeks by additional ultrasound. It was then confirmed at 20 weeks by MRI. A molecular diagnosis of JS was established after termination of the pregnancy. As genetic testing may not be feasible in JS, the ability to identify MTS sonographically as early as possible is important for affected families.

Non-invasive prenatal testing (NIPT) of cell-free fetal DNA in maternal plasma is a novel approach, designed for detecting common aneuploidies in the fetus. The Israeli Society of Medical Geneticists (ISMG) supports its use according to the guidelines stated herein. The clinical data collected thus far indicate that NIPT is highly sensitive in detecting trisomies 21 and 18, and fairly sensitive in detecting trisomy 13 and sex chromosome aneuploidies. Because false-positive results may occur, an abnormal result must be validated by invasive prenatal testing. At this juncture, NIPT does not replace existing prenatal screening tests for Down syndrome, as these are relatively inexpensive and cost-effective. Nonetheless, NIPT may be offered to women considered to be at high risk for fetal chromosomal abnormalities as early as 10 weeks of gestation. The ISMG states that NIPT should be an informed patient choice, and that pretest counseling regarding the limitations of NIPT is warranted. Women at high risk for genetic disorders not detected by NIPT should be referred for genetic counseling. A normal test result may be conveyed by a relevant healthcare provider, while an abnormal result should be discussed during a formal genetic consultation session.

The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Diaphonospondylodysostosis (DSD) is a rare, recessively inherited, lethal skeletal dysplasia, characterized by severe spinal ossification, segmentation defects, and renal cystic dysplasia with nephrogenic rests. We hereby present three affected individuals: two children and a fetus from two unrelated East Jerusalem Arab-Muslim families. Whereas most fetuses die in utero or perinatally, one of the children survived to 15 months. Homozygosity mapping in the two families demonstrated a single common 3.87 Mb region on chromosome 7, ruling out previously known spondylocostal/spondylothoracic dysostosis loci. The 15 protein coding genes in the region were prioritized, and some were sequenced. A single, novel deleterious mutation, Q104X, was detected in the bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene, recently reported to be mutated in other DSD patients [Funari et al., 2010]. The novel mutation we identified is an ancestral founder allele, as evidenced by a shared 440 SNP haplotype, and its frequency in the general Arab population is estimated to be <1:123. Our findings confirm loss of BMPER function as a cause of axial versus appendicular skeletal defects, and suggest that less deleterious mutations may be involved in milder axial skeleton abnormalities., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation.Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis., Objectives: To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis.Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness., Methods: DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis., Results: : A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation., Conclusions: This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness.

Although more than 15 years have elapsed since the discovery of the BRCA1 and BRCA2 genes and the associated increased risk of breast and ovarian cancers in mutation carriers, our understanding of the syndrome is still evolving. With the accumulation of knowledge, more questions arise regarding the proper approach to mutation carriers diagnosed as having cancer. Moreover, the number of questions regarding the recommended management methods for healthy carriers and the potential risk-reducing measures is increasing constantly.In this review, we discuss these issues and summarize contemporary recommendations.

Purpose of Review: As the length of survival in patients with gynecological malignancies increases due to advances in early diagnosis and therapy, quality of life becomes a major issue for the survivors. These women frequently suffer symptoms following an iatrogenically induced menopause. Many gynecologists advise these patients against hormonal replacement therapy. This review attempts to provide the clinician with information based on current evidence., Recent Findings: The most recent two prospective studies did not find an increase in the recurrence rates in endometrial cancer patients who used hormonal replacement therapy. To date, there are few studies on hormonal replacement therapy in patients with ovarian cancer but the available data suggest that there is no detriment to overall or disease-free survival. There are no data showing an association between poorer outcome and hormonal replacement therapy use in patients with cervical or vulvar cancers., Summary: There is no evidence showing hormones negatively influence survival after treatment for epithelial ovarian, squamous cervical or vulvar cancer. Their use can be considered in symptomatic patients with endometrial cancer, after weighing the benefits against the risk of recurrence. Gynecologic cancer survivors suffering from menopausal symptoms should be supported by advice about the alternatives to hormonal replacement therapy and by giving them nonbiased information on the present knowledge on the effects of hormonal use in women with a previous cancer. It is reasonable to prescribe hormonal replacement therapy to symptomatic, well informed patients.

Objective: To test whether elevated hCG alone triggers spontaneous ovarian hyperstimulation syndrome (sOHSS)., Design: Retrospective analysis., Setting: Departments of obstetrics and gynecology and of medical genetics in an academic medical center., Patient(s): A patient with sOHSS and 109 patients with elevated hCG., Intervention(s): Collecting blood samples., Main Outcome Measure(s): Follicle-stimulating hormone receptor gene sequence, levels of TSH and hCG., Result(s): We described a case of sporadic, nonfamilial sOHSS. Sequencing of the entire coding region the FSH gene revealed wild-type alleles for all the known mutations, and the A919G and A2039G polymorphisms, previously associated with good response to FSH stimulation and severe iatrogenic OHSS. We ruled out hypothyroidism. The level of hCG reached a peak of 344,350 IU/L (95th percentile). One hundred nine pregnancies with hCG of >150,000 IU/L were identified from 2001-2006. After patients with gestational trophoblastic diseases, multiple pregnancies, and iatrogenic OHSS were excluded, 27 patients remained. None of those patients experienced OHSS., Conclusion(s): Elevated hCG cannot be responsible for sOHSS as a single factor. Factors other than the hCG-FSH-receptor interaction additionally are involved in the pathogenesis of this syndrome. A combination of mechanisms may allow understanding of this enigmatic disorder. The pathophysiology of sOHSS, a rare phenomenon, has not yet been elucidated.

Objectives: To determine the significant predictors of clinical chorioamionitis and neonatal infection in patients with prelabor rupture of the membranes at term, and to apply this information to determination of optimal timing of labor induction., Study Design: A retrospective case control series of women at > or =37 weeks' with prelabor rupture of the membranes. The study group consisted of women with evidence of maternal or neonatal infection. Controls had no evidence of infection. Three types of management were compared. (1) Immediate induction of labor, (2) expectant management up to 24 h followed by induction of labor if still necessary, or (3) expectant management for over 24 h. Univariate and multivariate analyses were performed by stepwise logistic regression (SPSS software package). The size of the study and the control groups was calculated for a 90% power with two sided P value of 0.05 in order to demonstrate an odds ratio of 2 for expectant management (two groups: early and late) versus immediate induction of labor (132 and 279 women in the study and the control groups, respectively)., Results: The rate of expectant management for over 24 h versus expectant management until 24 h followed by induction of labor when still necessary, was higher among cases than among controls ( OR = 1.84; P < 0.017; 95% CI, 1.127-3.003). Conversely, the rate of immediate induction of labor versus expectant management until 24 h followed by induction of labor when still necessary, was also higher among cases ( OR = 2.66; P < 0.001; 95% CI, 0.222-0.644)., Conclusion: In women with prelabor rupture of the membranes at term, the best approach is to induce labor if spontaneous labor has not begun after 24 h.