Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases.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

Regions of Homozygocity size patterns among diverse ethnic groups in Israel: Toward tailored diagnostic reporting thresholds.

Long contiguous stretches of homozygosity or regions of homozygosity (ROH) are frequently detected via microarray and sequencing technologies. However, consensus on the establishment of specific size cutoffs for reporting ROH remains elusive. This study aims to assess the Total ROH Percentages (TRPS) and size of ROH segments across different ethnic origins, exploring potential disparities and proposing tailored diagnostic thresholds. This retrospective study included 13,035 microarray analyses conducted between 2017 to 2023. ROH segments on autosomal chromosomes were retrieved, and samples lacking ROH segments were excluded. The cohort was categorized based on reported ethnic origins, and TRPS and ROH segment size were analyzed for each origin. Distinct TRPS values were noted among different ethnic groups, ranging from median 0.36% in Ethiopian Jewish cohort and up to 6.42% in the Bedouin population. Wide range of 99th percentiles of ROH segment size for various origins was noted, ranging from 10.6 to 51.5 Mb. A significant correlation between ROH segment sizes and TRPS was noted in each origin. Statistically significant differences in ROH segment sizes were noted between the Jewish and the Israeli Arab/Druze origins in TRPS from 1% to 9.99%, whereas extremities of low (0.11%-0.99%) and high (over 10%) TRPS yielded no significant differences. In conclusion, as fixed absolute size thresholds may overlook pathogenic segments in certain populations while generating excessive reports in others, tailored approaches to define ROH reporting thresholds can be considered to facilitate the accuracy and clinical relevance of genomic analyses.

Exome sequencing in every pregnancy? Results of trio exome sequencing in structurally normal fetuses.

OBJECTIVE: This study aimed to assess the detection rate of clinically significant results of prenatal exome sequencing (pES) in low-risk pregnancies and apparently normal fetuses in non-consanguineous couples. METHODS: A retrospective analysis of pES conducted at a single center from January 2020 to September 2023 was performed. Genetic counseling was provided, and detailed medical histories were obtained. High-risk pregnancies were excluded due to major ultrasound anomalies, sonographic soft markers, abnormal maternal biochemical screening, or family history suggestive of monogenic diseases as well as cases with pathogenic and likely pathogenic (P/LP) chromosomal microarray results. Exome analysis focused on ∼2100 genes associated with Mendelian genetic disorders. Variant analysis and classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Among 1825 pES conducted, 1020 low-risk cases revealed 28 fetuses (2.7%) with potentially clinically significant variants indicating known monogenic diseases, primarily de novo dominant variants (64%). Among these 28 cases, 9 fetuses (0.9%) had the potential for severe phenotypes, including shortened lifespan and intellectual disability, and another 12 had the potential for milder phenotypes. Seven cases were reported with variants of uncertain significance (VUS) that, according to the ACMG criteria, leaned toward LP, constituting 0.7% of the entire cohort. Termination of pregnancy was elected in 13 out of 1020 cases (1.2%) in the cohort, including 7/9 in the severe phenotypes group, 2/12 in the milder phenotype group, and 4/7 in the VUS group. CONCLUSION: The 2.7% detection rate highlights the significant contribution of pES in low-risk pregnancies. However, it necessitates rigorous analysis, and comprehensive genetic counseling before and after testing.

The Diagnostic Yield of Chromosomal Microarray Analysis in Third-Trimester Fetal Abnormalities.

OBJECTIVE: This study aimed to determine the diagnostic yield of chromosomal microarray analysis (CMA) performed in cases of fetal abnormalities detected during the third trimester of pregnancy. STUDY DESIGN: A retrospective review of medical records was conducted for women who underwent amniocentesis at or beyond 28 weeks of gestation between January 2017 and February 2023. CMA results of pregnancies with abnormal sonographic findings not detected before 28 weeks were included. RESULTS: A total of 482 fetuses met the inclusion criteria. The average maternal age was 31.3 years, and the average gestational age at amniocentesis was 32.3 weeks. The overall diagnostic yield of CMA was 6.2% (30 clinically significant copy number variations [CNVs]). The yield was 16.4% in cases with two or more fetal malformations, while cases with a single anomaly revealed a diagnostic yield of 7.3%. Cases presenting isolated polyhydramnios or isolated fetal growth restriction had a lower yield of 9.3 and 5.4%, respectively. Of the 30 clinically significant cases, 19 (or 63.4%) exhibited recurrent CNVs. The remaining 11 cases (or 36.6%) presented unique CNVs. The theoretical yield of Noninvasive Prenatal Testing (NIPT) in our cohort is 2% for aneuploidy, which implies that it could potentially miss up to 70% of the significant findings that could be identified by CMA. In 80% of the fetuses (or 24 out of 30) with clinically significant CNVs, the structural abnormalities detected on fetal ultrasound examinations corresponded with the CMA results. CONCLUSION: The 6.2% detection rate of significant CNVs in late-onset fetal anomalies confirms the value of CMA in third-trimester amniocentesis. The findings underscore the necessity of CMA for detecting CNVs potentially overlooked by NIPT and emphasize the importance of thorough genetic counseling. KEY POINTS: · CMA yields 6.2% for third-trimester anomalies.. · NIPT may miss 70% of CMA findings.. · Ultrasound matched 80% of CMA results..

Does the combination of four OGTT values enhance the prediction of adverse pregnancy outcomes? Insights from a retrospective cohort study.

AIM: To explore the correlation between a singular value of additive OGTT scores and adverse maternal and neonatal outcomes. We postulated that a higher additive OGTT score would predict poorer maternal and neonatal outcomes. METHODS: In this retrospective cohort study, data were collected from all women with a documented complete OGTT result and subsequent diagnosis of GDM. The additive OGTT score was calculated by adding each individual hourly glucose measurement. Maternal demographics, pregnancy and labor characteristics, and neonatal outcomes were compared between the lower-sum and higher-sum OGTT groups. A multivariate regression analysis was performed to identify confounders associated with adverse outcomes. RESULTS: In this study, a total of 1497 patients were assessed. The group with higher-sum OGTT scores was characterized by increased rates of GDMA2 (p = 0.008), higher insulin doses (p = 0.009), and higher rates of composite maternal and neonatal adverse outcomes (p = 0.021 and p = 0.030, respectively) compared to the lower-sum OGTT group. CONCLUSION: The additive OGTT score may aid in predicting the need for insulin treatment, labor course, and neonatal outcomes in GDM patients.

Predictors of maternal and neonatal outcomes in labors complicated by shoulder dystocia: a comparative analysis.

INTRODUCTION: Studies investigating the risk factors associated with unfavorable maternal/neonatal outcomes in cases of shoulder dystocia are scarce. This study aims to uncover the predictive factors that give rise to unfavorable outcomes within the context of shoulder dystocia. MATERIALS AND METHODS: Medical records of pregnancies complicated by shoulder dystocia was obtained between 2008-2022 from a single tertiary center. This study involved the comparison of sociodemographic, sonographic, and delivery characteristics among pregnancies complicated by shoulder dystocia resulting in favorable vs. unfavorable maternal/neonatal outcomes. RESULTS: A total of 275 pregnancies were analyzed, with 111 (40.3%) classified as unfavorable outcomes and 164 (59.7%) as favorable outcomes. Employing a multivariable regression analysis, several independent associations were identified with unfavorable maternal/neonatal outcomes. Specifically, short maternal stature, pre-gestational diabetes, vacuum extraction, Wood's screw maneuver, and macrosomia merged as significant predictors of unfavorable maternal/neonatal outcomes. CONCLUSION: Short maternal stature, pre-gestational diabetes, vacuum extraction, Wood's screw maneuver, and macrosomia may all contribute to poor maternal/neonatal outcomes in shoulder dystocia cases. This knowledge allows clinicians to improve their decision-making, patient care, and counseling.

Pregnancy outcomes in correlation with placental histopathology in pregnancies complicated by fetal growth restriction with vs. without reduced fetal movements.

PURPOSE: Fetal movements are crucial indicators of fetal well-being, with reduced fetal movements (RFM) suggesting potential fetal compromise. Fetal growth restriction (FGR), often linked to placental insufficiency, is a major cause of perinatal morbidity and mortality. This study aimed to investigate the neonatal, labor, and placental outcomes of FGR pregnancies with and without RFM at term. METHODS: In this retrospective study, data from all term, singleton deliveries with FGR and concomitant RFM were obtained and compared to an equal control group of FGR without RFM. Maternal characteristics, pregnancy and neonatal outcomes, and placental histology were compared. The primary outcome was a composite of adverse neonatal outcomes. A multivariable regression analysis was performed to identify independent associations with adverse neonatal outcomes. RESULTS: During the study period, 250 FGR neonates with concomitant RFM and an equal control group were identified. The groups did not differ in maternal demographics aside from significantly higher rates of maternal smoking in the RFM group (p < 0.001). Polyhydramnios and oligohydramnios (p = 0.032 and p = 0.007, respectively) and meconium-stained amniotic fluid (p < 0.001) were more prevalent in the FGR+RFM group. Additionally, the RFM group showed higher rates of adverse neonatal outcomes despite having larger neonates (p = 0.047 and p < 0.001, respectively). No significant differences were observed in placental findings. Logistic regression identified RFM as an independent predictor of adverse neonatal outcomes (aOR 2.45, 95% CI 1.27-4.73, p = 0.008). CONCLUSION: Reduced fetal movements are significant and independent predictors of worse neonatal outcomes in FGR pregnancies, suggesting an additional acute insult on top of underlying placental insufficiency.

Chromosomal microarray testing yield in 829 cases of microcephaly: a clinical characteristics-based analysis for prenatal and postnatal cases.

INTRODUCTION: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. MATERIALS AND METHODS: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. RESULTS: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. CONCLUSIONS: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result.

The effect of Home Ultrasound Prenatal Care on Maternal Anxiety in Patients with Previous Recurrent Pregnancy Loss- A Randomized control trial.

BACKGROUND: Patients with previous recurrent pregnancy loss are subject to increased maternal anxiety and reduced antenatal attachment during the subsequent pregnancy. Maternal anxiety is associated with worse pregnancy and neonatal outcomes. Home ultrasound is a feasible tool with the potential to alleviate maternal anxiety by ensuring fetal well-being. OBJECTIVE: This study aimed to investigate the impact of complementing standard prenatal care with twice-weekly telemedicine visits incorporating home ultrasound on maternal anxiety and antenatal attachment in individuals with a history of recurrent pregnancy loss. STUDY DESIGN: In this randomized controlled trial, patients with a history of two or more prior abortions were randomized early in their subsequent pregnancy in a 1:1 ratio into either the control group, which received standard high-risk prenatal care, or the study group, which received additional twice-weekly home-ultrasound sessions. The home-ultrasound scans assessed fetal pulse, movements, and amniotic fluid volume, aiming to provide maternal reassurance. Patients performed the scans themselves using the Pulsenmore device, with real-time guidance from a physician. Maternal anxiety was assessed using the validated State-Trait Anxiety Inventory Scale (STAI-S) and the Revised Prenatal Distress Questionnaire (NuPDQ), while maternal attachment was measured with the validated Maternal Antenatal Attachment Scale (MAAS-2) at three time points during pregnancy. The primary outcome was the STAI-S score at the final prenatal visit. A sample size of 50 patients was calculated to detect a 20% difference in the primary outcome. RESULTS: Of the 57 patients recruited, 50 completed the follow-up, 25 in each group. There were no significant differences in demographics between the groups. The primary outcome (STAI score at the last visit) was significantly lower in the device group compared to the control group (p = 0.037). In addition, the study group exhibited a greater reduction in STAI scores between the first and last visits (p = 0.045), and a significantly higher MAAS score at the end of the follow-up period (p = 0.046). CONCLUSION: Integrating routine home-ultrasound telemedicine visits into prenatal care can significantly reduce maternal anxiety during pregnancy and contribute to greater maternal attachment in individuals with a history of recurrent pregnancy loss. These results emphasize the potential benefits of home ultrasound as a tool to alleviate anxiety, provide a sense of control, and foster a deeper maternal connection among pregnant individuals who have experienced previous pregnancy loss.

Improved neonatal outcomes in pregnancies with coexisting gestational diabetes and preeclampsia in normal birthweight neonates- insights from a retrospective cohort study.

INTRODUCTION: We aimed to assess neonatal and maternal outcomes in appropriate-for-gestational-weight (AGA) neonates of mothers with both gestational diabetes mellitus (GDM) and preeclampsia (PET). METHODS: Medical records of women diagnosed with GDM or PET were reviewed. Women with AGA neonates were divided into three groups- GDM, PET, and GDM + PET and maternal neonatal and placental outcomes were compared. The primary outcome was a composite of adverse neonatal outcomes, including intensive care unit admission (NICU), neurological morbidity, hypoglycemia, ventilation, respiratory distress syndrome (RDS), phototherapy, sepsis, blood transfusion, and neonatal death. Post-hoc analysis was performed to determine between-group significance. RESULTS: Composite adverse neonatal outcomes are significantly lower in women with multiple morbidities compared to women with confined PET (p = 0.015), and a similar trend is observed when comparing neonatal outcomes between women with GDM to those with GDM + PET, yet these results are underpowered (18.9 % vs. 12.8 % respectively, p = 0.243). Placentas of women with GDM + PET were larger, with a lower rate of placentas below the 10th percentile as compared to placentas of women with isolated PET (p < 0.001), but with similar rates of MVM lesions. DISCUSSION: While maternal and placental outcomes in patients of the GDM + PET group resemble the characteristics of the PET group, surprisingly, the neonatal outcomes in this group are significantly better compared to isolated morbidities. The paradoxical benefit attributed to the coexistence of GDM + PET may be explained by a balance of the opposing trends characterizing these morbidities-the reduced blood and nutrient supply characterizing PET vs. chronic overflow and abundance typical of GDM. CLINICAL TRIAL REGISTRATION: approval of local ethics committee WOMC-19-0152.

The association between maternal and child posttraumatic stress symptoms among families living in southern Israel: The buffering role of maternal executive functions.

Posttraumatic stress disorder is a prolonged stress and anxiety response that occurs after exposure to a traumatic event. Research shows that both parental and child posttraumatic stress symptoms (PTSS) are correlated but parental executive functions (EFs) could buffer this link. EFs refers to a group of high-level cognitive processes that enable self-regulation of thoughts and actions to achieve goal-directed behaviours and can be of importance for both positive parenting interactions and effective coping skills for PTSS. Our study aimed to (1) examine the link between maternal and child PTSS and the moderating role of varying degrees of exposure to severe security threats context, and (2) to identify the moderating role of maternal EFs in this interaction, among families living in southern Israel. Our sample included 131 mothers in their second pregnancy and their firstborn children. Mothers performed computerised tasks to assess their EFs and they reported on their own and their child's PTSS. Results revealed a positive correlation between maternal PTSS and child PTSS. However, the link between maternal and child PTSS was moderated by maternal working memory updating abilities and threat context severity. Among mothers with lower updating capacities, the association between maternal and child symptoms was stronger under higher threat contexts; conversely, among mothers with higher maternal updating abilities, threat context did not modulate the link between maternal and child PTSS, suggesting a stress-buffering effect. Our study contributes to the growing literature on the significant role of parental EFs in the context of parent-child interactions.