Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases.

BACKGROUND: Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance. METHODS: We identified cases of distal Xq28 duplication (chrX: 154,126,575-154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication. RESULTS: Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200-300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males. CONCLUSION: Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.

Impact of body mass index and examination type on utilization of screening programs: A big data study.

OBJECTIVE: To investigate the relationship between Body Mass Index (BMI) and adherence to recommended screening tests, addressing gaps in previous literature by utilizing a large cohort, while considering longitudinal changes in weight and the type of screening. METHODS: Data from Clalit Health Services in Israel were retrospectively analyzed, including participants aged 50 and above from 2002 to 2021. BMI measurements and various screening test records were examined. Generalized Estimating Equations were employed for analysis, adjusting for potential confounding variables, including age, gender, geographic location, and socioeconomic status. RESULTS: The study included 634,879 participants with 4,630,030 BMI measurements and 56,453,659 test records. Participants were categorized into BMI cohorts at the time of the test, with overweight and obese individuals showing lower odds of undergoing intimate examination-based screening tests (mammography, PAPS, and skin examination), as opposed to higher odds of several non-intimate tests (e.g., diabetes and eye disorder screenings). DISCUSSION: Our findings suggest that individuals with overweight and obesity are less likely to undergo screenings involving intimate physical examinations, potentially due to weight stigma and discomfort. This avoidance behavior may contribute to increased morbidity rates in these populations. Interventions addressing weight stigma, improving access to care, and enhancing patient engagement are warranted.

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.

"We hear and we fear" - Insights of 1203 Women on Personnel Conversations During Cesarean Delivery.

OBJECTIVE: To assess the preferences of women undergoing cesarean delivery regarding intraoperative conversations among healthcare personnel. METHODS: This cross-sectional study was conducted by distribution of an open anonymous questionnaire on social media platforms during March 2022, targeting respondents with a history of cesarean delivery. The primary outcome was patients' experience of "being disturbed by professional and casual conversations of the personnel", rated on a 1-5 Likert scale. RESULTS: 1203 participants completed the questionnaire, with 97.6% reporting intraoperative conversations among personnel. Casual conversations were perceived as "disturbing" by more respondents vs. professional talk (33.4% vs. 27.6%, respectively, p = 0.0077). Logistic regression analysis revealed associations between feeling disturbed and higher intraoperative stress and pain - adjusted Odds Ratio (OR) 3.1, 95% confidence interval (CI) 2.1-4.5, and OR 2.7, 95%CI 1.8-4.0, respectively, for professional conversations; OR 3.0, 95%CI 2.0-4.4, and OR 1.7, 95%CI 1.1-2.7, respectively, for casual conversations. Feeling disturbed by professional conversations was also associated with urgent vs. elective operations (OR 2.0, 95%CI 1.4-3.0). Direct personnel-patient communication was associated with significantly lower stress levels (60.8% vs. 72.5% in the remaining cohort, p < 0.001). DISCUSSION: Intraoperative conversations of the personnel occur during vast majority of cesarean deliveries. Given that a substantial proportion of patients find these conversations disturbing, it is advisable to conduct a preliminary assessment of maternal preferences. This proactive step can help tailor communication strategies to individual patient comfort and preferences, ultimately enhancing the birthing experience and maternal well-being.

The association between obesity and the success of trial of labor after cesarean delivery (TOLAC) in women with past vaginal delivery.

OBJECTIVES: To evaluate the effect of overweight (body mass index; BMI 25.0-29.9 kg/m2), and obesity (BMI>30 kg/m2), on the success of trial of labor after cesarean delivery (TOLAC), with consideration of successful past vaginal birth. METHODS: This retrospective cohort study was performed using electronic database of obstetrics department at a university-affiliated tertiary medical center. All women admitted for TOLAC at 37-42 weeks of gestational age, carrying a singleton live fetus at cephalic presentation, with a single previous low segment transverse cesarean delivery between 1/2015 and 5/2021 were included. Primary outcome was the rate of cesarean delivery during labor, and subgroup analysis was performed for the presence of past vaginal birth. RESULTS: Of the 1200 TOLAC deliveries meeting the inclusion criteria, 61.9 % had BMI in the normal range, 24.6 % were overweight (BMI 25.0-29.9 kg/m2), and 13.4 % were obese (BMI of 30 kg/m2 and over). Using a multivariate analysis, BMI≥30 kg/m2 was associated with increased risk of cesarean delivery compared to normal weight. However, in the subgroup of 292 women with a history of successful vaginal birth BMI did not affect TOLAC success. CONCLUSIONS: BMI does not affect the success of TOLAC in women with previous vaginal birth. This information should be considered during patients counselling, in order to achieve a better selection of mode of delivery and higher patients' satisfaction.

[THE EFFECTS OF GENDER ON THE MANIFESTATIONS AND CONSEQUENCES OF WEIGHT STIGMA].

INTRODUCTION: Weight stigma, or weight bias, refers to biased beliefs and negative opinions towards people with excess weight. This phenomenon manifests in prejudice and negative attitudes towards people with obesity, including disrespectful treatment, bullying, discrimination and even abuse, and leading to long-term negative consequences on physical and mental health. The purpose of the current review was to examine the relationship between gender and manifestations of weight stigma. Studies listed in this review show that the phenomenon of weight stigma is more common and severe among women, in numerous life areas, which include education, employment, the healthcare system, social media, sports industry, and interpersonal relationships. Possible reasons for such differences include the existing discrimination against women in various areas of life, and the emphasis on external appearance and the ideal of thinness, which relates mainly to women. In light of the serious consequences of weight stigma on public health and individual well-being, efforts must be made to prevent weight stigma, including the education of the general population, changing policies of healthcare, education and media systems, and legislation to prevent weight-based discrimination.

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

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

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy.

PURPOSE: To summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. METHODS: Data acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. RESULTS: Of overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. CONCLUSION: Interpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

A call for public funding of invasive and non-invasive prenatal testing.

For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test.

[ADVANCES AND CHALLENGES IN THE FIELD OF GENETIC TESTING - AN INTRODUCTORY ARTICLE].

INTRODUCTION: In the current issue of Harefuah, we present original research articles and reviews, reflecting the tremendous development of the field of genetic testing. This progress provides extensive tools for determining genetic diagnoses, thereby enabling detailed explanation for patients and their family members regarding the specific genetic disorder, adjustment of medical evaluation and follow-up, and allowing informed decision-making during pregnancy. Furthermore, there are advances in the assessment of recurrence of risks among members of the extended family, including future pregnancies, with a possibility of prenatal diagnosis and pre-implantation genetic testing.

[SUMMARY AND UPDATES IN THE FIELD OF GENETIC TESTING IN ISRAEL - AS OF 2022].

INTRODUCTION: Considerable progress has been observed in the field of genetic counseling and testing in Israel, including the availability and funding of services. The purpose of the article is to summarize the management and present the updates in the field of genetic testing in Israel, as of 2022. The progress in the field of pregnancy-related genetic testing includes an ancestry-based annually updated genetic screening, which has significantly reduced the incidence of several severe and common hereditary diseases. A comprehensive and uniform genetic screening test was submitted for approval by the next basket committee.

[CHARACTERIZATION OF THE INDICATIONS FOR PERFORMING GENE PANEL SEQUENCING TESTS IN A GENOMIC CENTER].

INTRODUCTION: Following the recent human genome revolution, novel technologies have been developed in the last decade enabling advanced sequencing tests, including genetic panel tests that focus on groups of specific genes associated with a certain medical condition (phenotype). Since the process of assembling a genetic panel may be complex and requires significant manpower and time, it is important to define the most common and requested panels, for gradual construction and introduction of panel tests starting with the most common. AIMS: Since no information was found in the literature defining the common panels, the aim of the study was to define the indications for performing a gene panel within the framework of the provided services, and to estimate their frequency. METHODS: Prospective data acquisition was performed by a party responsible for approval of panel tests within Clalit Health Services Organization. The indications for all approved panel tests were registered since the launch of Clalit's Genomic Center. The total number of indications was counted, and according to the Pareto principle, 20% of the most frequent indications were chosen. In addition, the indications were divided into main medical disciplines. RESULTS: Overall, 132 indications were recorded for approved gene panel tests; 20% of these indications, i.e. the first 26 indications in terms of frequency, covered 79.6% of the cases. The most frequent approved panels were epilepsy (10.4%, confidence interval (CI) 8.5-12.6%), Maturity-onset diabetes of the young (MODY) (9.6%, CI 7.8-11.7%), cardiomyopathy (8.3%, CI 6.6-10.3%) and hearing impairment (7.6%, CI 6.0-9.6%). The most common disciplines in descending order were neurological diseases (23.0%, CI 20.3-25.9%), endocrinology (13.1%, CI 11.1-15.6%), heart diseases (9.0%, CI 7.3-11.1%) and eye diseases (7.8%, CI 6.2-9.8%). CONCLUSIONS: A review of panel approvals at the Genomic Center of Clalit showed a number of frequent indications. DISCUSSION: We believe this information can be useful for the establishment of genomic laboratories, as well as for the improvement of the service to the patients, by enabling the referral for specific panel tests by medical experts who are not geneticists or genetic counselors, after appropriate training (such as the "Genetics First" program of Clalit).

[HOW SIMPLE IS "SIMPLE" GENETIC COUNSELING?]

INTRODUCTION: Genetic counselors are often compared with other medical professionals in terms of productivity, based on the number of patients seen and the time required for each patient. Prenatal genetic counseling before amniocentesis in uneventful pregnancies is considered to be a "simple" counseling, with potentially less time required for each patient. Thus, in some medical centers the duration of such consultations is limited to provide only the basic explanation without detailed collection of personal and family history, while in others the explanation is given to several patients together. AIMS: To assess the need for extended genetic counseling during supposedly "simple" genetic consultations before amniocentesis. METHODS: Data was collected from January 2018 until August 2020 of all patients undergoing genetic counseling before amniocentesis due to advanced maternal age, abnormal biochemical screening, or without medical indication. The consultations were given by four genetic counselors and two medical geneticists. The need for extended genetic counseling was evaluated based on pedigree and the discussion summaries and recommendations noted in genetic counseling summaries. RESULTS: Of the 1085 relevant counseling appointments, 657 (60.5%) required additional explanation beyond the basic consultation. The reasons for extended counseling included medical disorders of the woman or spouse (21.2%), carrier state for autosomal recessive diseases (18.6%), diagnosed or suspected genetic conditions of a child or previous pregnancy (9.6%), or medical disorders in the extended family (79.1%). In 31.0% of patients, recommended carrier screening tests were recommended or added. In 32.3% of cases, only one extra subject was counseled, in 16.3% two subjects, and in 5%, three subjects or more. The additional explanations were estimated as short (up to 5 minutes) in 36.9% of the cases, intermediate (5 to 15 minutes) in 59.9%, and long (over 15 minutes) in 2.6% of cases. The consultation's duration was not affected from it being a first meeting or a recurrent consultation. CONCLUSIONS: The need for further explanation was demonstrated in over 60% of genetic consultations, performed prior to amniocentesis due to supposedly "simple" indication. DISCUSSION: This fact reflects the importance of formal genetic counseling even in cases of seemingly simple indications, with an emphasis on detailed personal and family history, dedicating sufficient time to the counseling itself. Alternatively, it is important to exercise extra caution when conducting a short explanatory conversation prior to amniocentesis, including detailed questionnaires and the patient's signature on the possible limitations of such explanations.

Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.

OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. METHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. RESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. INTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.

Residual risk for clinically significant copy number variants in low-risk pregnancies, following exclusion of noninvasive prenatal screening-detectable findings.

BACKGROUND: Chromosomal microarray analysis detects a clinically significant amount of copy number variants in approximately 1% of low-risk pregnancies. As the constantly growing use of noninvasive prenatal screening has facilitated the detection of chromosomal aberrations, defining the rate of abnormal chromosomal microarray analysis findings following normal noninvasive prenatal screening is of importance for making informed decisions regarding prenatal testing and screening options. OBJECTIVE: To calculate the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening. STUDY DESIGN: The chromosomal microarray results of all pregnancies undergoing amniocentesis between the years 2013 and 2021 in a large hospital-based laboratory were collected. Pregnancies with sonographic anomalies, abnormal maternal serum screening, or multiple fetuses were excluded. Clinically significant (pathogenic and likely pathogenic) copy number variants were divided into the following: 3-noninvasive prenatal screening-detectable (trisomies 13, 18, and 21), 5- noninvasive prenatal screening-detectable (including sex chromosome aberrations), 5-noninvasive prenatal screening and common microdeletion-detectable (including 1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1, and 22q11.2 deletions), and genome-wide noninvasive prenatal screening-detectable (including variants >7 Mb). The theoretical residual risk for clinically significant copy number variants was calculated following the exclusion of noninvasive prenatal screening-detectable findings. RESULTS: Of the 7235 pregnancies, clinically significant copy number variants were demonstrated in 87 cases (1.2%). The residual risk following theoretically normal noninvasive prenatal screening was 1.07% (1/94) for 3-noninvasive prenatal screening, 0.78% (1/129) for 5- noninvasive prenatal screening, 0.74% (1/136) for 5- noninvasive prenatal screening including common microdeletions, and 0.68% (1/147) for genome-wide noninvasive prenatal screening. In the subgroup of 4048 pregnancies with advanced maternal age, the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening ranged from 1.36% (1/73) for 3- noninvasive prenatal screening to 0.82% (1/122) for genome-wide noninvasive prenatal screening. In 3187 pregnancies of women <35 years, this residual risk ranged from 0.69% (1/145) for 3- noninvasive prenatal screening to 0.5% (1/199) for genome-wide noninvasive prenatal screening. CONCLUSION: The residual risk of clinically significant copy number variants in pregnancies without structural sonographic anomalies is appreciable and depends on the noninvasive prenatal screening extent and maternal age. This knowledge is important for the patients, obstetricians, and genetic counselors to facilitate informed decisions regarding prenatal testing and screening options.

The condemned fundal pressure maneuver: time to reconsider?

Due to a concern of severe adverse neonatal and maternal complications, fundal pressure (FP) maneuver has been discouraged by several national obstetric guidelines as well as the World Health Organization. In this manuscript, we argue that previously published evidence pointing to unfavorable effects of FP might not be relevant to the common practice. Our main concern is that the inherent limitations of published studies undermining the association of FP with various obstetric complications, in conjunction with fear of medical-legal implications, might lead to an absolute avoidance of this procedure, with a potential subsequent increase in vacuum-assisted and cesarean deliveries. We suggest establishing standardized guidelines for FP application, intend to prevent application of uncontrollable and aggressive pressure, assist the obstetricians in case of legal claims, and yet to preserve the use of gentle and respectful FP application to benefit the delivery.

Combination of early pushing with extended second stage increases the rates of spontaneous vaginal deliveries, but might be associated with adverse maternal and neonatal outcomes.

OBJECTIVE: To evaluate the effect of combining the technique of early pushing and extended second stage on the mode of delivery, as well as adverse maternal and neonatal outcomes. STUDY DESIGN: This retrospective data analysis included all women delivering in a single tertiary medical center through 2015-2020. In January 2017 the protocol of second-stage management was changed to a combination of extended second stage (i.e., addition of an extra-hour to the traditional Friedman cutoffs), as well as early pushing (i.e., initiation of active pushing within the first 30 min of full dilatation). We compared delivery outcomes in women reaching full dilatation during January 2015-December 2016, vs. January 2017-July 2020. RESULTS: Of the 15,792 parturients, 10,418 (66.0%) were managed using the "new" protocol. No difference was found in terms of baseline characteristics, except for higher rates of neuraxial analgesia (72.8% vs. 70.4%, p = 0.002) and induction of labor (22.4% vs. 17.8%, p < 0.0001) during the new protocol period. In subgroup analysis by parity and neuraxial analgesia, no change was noted in the rate of cesarean deliveries. A significant increase in spontaneous vaginal deliveries (SVD) in favor of the "new" protocol was noted, except for multiparous women with no analgesia. In addition, in primiparous women with neuraxial analgesia, a decrease in vacuum deliveries was noted. In secondary outcome analysis, a significant increase in postpartum hemorrhage and a decrease in umbilical base excess values was noted in women with neuraxial analgesia, both primi- and multiparous. DISCUSSION: Early pushing along with extension of the second stage was associated with higher rate of SVD, at the expense of increased risk for maternal postpartum hemorrhage. Thus, combination of these two techniques must be practiced with caution.

Prenatal and postnatal chromosomal microarray analysis in 885 cases of various congenital heart defects.

PURPOSE: This study aimed to evaluate the prevalence of clinically significant (pathogenic and likely pathogenic) variants detected by chromosomal microarray (CMA) tests performed for prenatally and postnatally detected congenital heart defects. METHODS: A retrospective evaluation of CMA analyses over a period of four years in a single tertiary medical center was performed. Detection rate of clinically significant variants was calculated in the whole cohort, prenatal vs. postnatal cases, and isolated vs. non-isolated CHD. This rate was compared to previously published control cohorts, and to a theoretical detection rate of noninvasive prenatal testing (NIPS; 5 chromosomes). RESULTS: Of the 885 cases of CHD, 111 (12.5%) clinically significant variants were detected, with no significant difference between the 498 prenatal and the 387 postnatal cases (10.8% vs. 14.7%, p = 0.08). In both groups, the detection rate was significantly higher for non-isolated vs. isolated CHD (76/339 = 22.4% vs. 35/546 = 6.4%, respectively, p < 0.05). The detection rate was higher than the background risk in both groups, including cases of postnatal isolated CHD. 44% of abnormal findings in the prenatal setting would be detectable by NIPS. CONCLUSION: CMA should be performed for both prenatally and postnatally detected CHD, including postnatal cases of isolated CHD, while NIPS can be considered in specific scenarios.