Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.

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.

Exploring the factors affecting classification and reporting of uncertain prenatal microarray findings, using a "virtual fetus" model-a pilot study.

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.

Care after premenopausal risk-reducing salpingo-oophorectomy in high-risk women: Scoping review and international consensus recommendations.

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.

Trial of labor following cesarean in preterm deliveries: success rates and maternal and neonatal outcomes: a multicenter retrospective study.

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.

[GENOTYPE-PHENOTYPE CORRELATIONS BY SPECIFIC FOUNDER VARIANTS IN BRCA IN ISRAELI WOMEN].

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.

Combining cytogenetic and genomic technologies for deciphering challenging complex chromosomal rearrangements.

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.

Chromosomal microarray should be performed for cases of fetal short long bones detected prenatally.

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.

The Yield of Chromosomal Microarray in Pregnancies Complicated with Fetal Growth Restriction Can Be Predicted According to Clinical Parameters.

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.

Teaching clinicians practical genomic medicine: 7 years' experience in a tertiary care center.

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.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.

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.

Prolonged operative time of repeat cesarean is a risk marker for post-operative maternal complications.

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.

Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.

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.

Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel.

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.

BRCA mutation carriers do not have compromised ovarian reserve.

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.

Early second-trimester molar tooth sign.

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.

Israeli Society of Medical Genetics NIPT Committee Opinion 072013: Non-invasive prenatal testing of cell-free DNA in maternal plasma for detection of fetal aneuploidy.

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.

Use of antibiotics in women undergoing correction of an obstetric anal sphincter injury: Results from a national Israeli survey.

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.

Cytomegalovirus (CMV) seroprevalence among women at childbearing age, maternal and congenital CMV infection: policy implications of a descriptive, retrospective, community-based study.

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.

Repeat low order caesarean delivery, risk factors for complications: A retrospective, longitudinal study.

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.

Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis.

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_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_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.