Search

This article, titled "EP09.38: Placental pathology in pregnancies complicated by right heart obstructive lesions," explores the characteristics of placentas in pregnancies with right heart obstructive congenital lesions (RHO) and their correlation with morphological and ultrasound anomalies. The study analyzed 112 fetal placentas affected by coronary heart disease (CHD) from March 2021 to October 2023. The results showed that RHO+ placentas displayed signs of vascular malperfusion (VM) on the fetal side, with higher avascular villi and fetal inflammatory infiltrate. The study suggests that further investigation is needed to understand the unique pathophysiology of RHO+ placentas. [Extracted from the article]

This article explores the relationship between placental malperfusion (PM) and congenital heart disease (CHD) in pregnancies. The study analyzed 95 fetal placentas affected by CHD and categorized placental pathology as maternal placental malperfusion (MPM), fetal placental malperfusion (FPM), and combined maternal-fetal placental malperfusion (MFPM). The results showed a higher prevalence of PM in patients with pathologies involving pulmonary overflow volume (OV) and transposition of great arteries (TGA). The study confirms an association between placental vascular anomalies and fetal CHD, but notes that the higher prevalence of PM in patients with OV may be influenced by comorbidities. [Extracted from the article]

It is reported that many infants with CDH have evidence of brain injury on postnatal brain magnetic resonance imaging (MRI). Results HT

To describe ultrasound features of fetal ovarian cysts as reported by the original ultrasound examiner and according to IOTA terminology. Ovarian cysts with low level content could be managed expectantly, whereas ovarian cysts with other cyst content should be managed with postnatal surgery, due to the high risk of necrosis at final histology. [Extracted from the article]

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes., (© 2024. The Author(s).)

Objective: To relate the distance traveled from the patient's residence to the gestational trophoblastic neoplasia (GTN) reference center (RC) and the occurrence of unfavorable clinical outcomes, as well as to estimate the possible association between this distance and the risk of metastatic disease at presentation, the need for multiagent chemotherapy to achieve remission and loss to follow-up before remission., Study Design: Retrospective historical cohort study of patients with GTN followed at 8 Brazilian GTN-RC, from January 1st, 2000 - December 31st, 2017., Results: Evaluating 1055 cases of GTN, and using a receiver operating characteristic curve, we found a distance of 56 km (km) from the residence to the GTN-RC (sensitivity = 0.57, specificity = 0.61) best predicted the occurrence of at least one of the following outcomes: occurrence of metastatic disease, need for multiagent chemotherapy to achieve remission, or loss to follow-up during chemotherapy. Multivariate logistic regression adjusted by age, ethnicity, marital status and the reference center location showed that when the distance between residence and GTN-RC was ≥56 km, there was an increase in the occurrence of metastatic disease (relative risk - RR:3.27; 95%CI:2.20-4.85), need for multiagent chemotherapy (RR:1.36; 95%CI:1.05-1.76), loss to follow-up during chemotherapy (RR:4.52; 95CI:1.93-10.63), occurrence of chemoresistance (RR:4.61; 95%CI:3.07-6.93), relapse (RR:10.27; 95%CI:3.08-34.28) and death due to GTN (RR:3.62; 95%CI:1.51-8.67)., Conclusions: The distance between the patient's residence and the GTN-RC is a risk factor for unfavorable outcomes, including death from this disease. It is crucial to guarantee these patients get prompt access to the GTN-RC and receive follow-up support., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Discharge against medical advice (DAMA) represents an increasingly burdensome public health issue that leads to worse outcomes for patients and high costs to society. While the rate of patients who DAMA is higher within certain institutions and geographic locations, the problem is present across all healthcare systems. DAMAs are often challenging as they occur suddenly and can be unsatisfactory. An opportunity exists to better meet the needs of this patient population; however, many providers are unsure of how they can prevent a DAMA. In this review, we discuss the broader impact, associated factors, the most common reasons, the consequences, and the prevention strategies for DAMA. Further research is needed to create tools for stratifying patients most likely to DAMA. Early identification and appropriate interventions for these patients will allow for safe discharges., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia)., Methods: 52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter-BPD, brain fronto-occipital diameter-BFOD, third ventricle, posterior ventricles, transcerebellar diameter-TCD, anteroposterior and craniocaudal cerebellar vermis diameter-AP and CC) and cortical structures (bilateral cingulate fissure-CF, insular fissure-IF, insular depth - ID) were compared with controls using Mann-Whitney test., Results: Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03)., Conclusions: CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

The purpose of this study was to determine the feasibility of a novel exergaming intervention guided by heart rate zones for children and adolescents with fetal alcohol spectrum disorder (FASD) and attention-deficit/hyperactivity disorder (ADHD). Eight study participants (6 females, 2 males, mean age= 11.4±1.4 years old) participated twice weekly over six weeks to complete twelve multimodal exergaming sessions. Participants significantly improved 6MWT from baseline to week 6 (575.4±55.0 m to 732.8±58.9 m; P<0.01), which conferred a 31% improvement in estimated VO 2max (31.5±5.5 ml/kg/min to 40.9±5.9 ml/kg/min), respectively. There was an upward trend of the mean percentage of time spent in the intermediate HR zones over the course of the 6-week intervention. These findings may provide value to the field as they support the clinical utility and promising effects of cardiovascular improvement in children who engage in a compelling exergaming intervention. In doing so, this establishes a preliminary understanding of how to augment routine physical exercise through exergaming using visually targeted heart rate zones.

Objective: To assess whether the incidence and aggressiveness of molar pregnancy (MP) and postmolar gestational trophoblastic neoplasia (GTN) changed during the COVID-19 pandemic., Design: Observational study with two separate designs: retrospective multicentre cohort of patients with MP/postmolar GTN and a cross-sectional analysis, with application of a questionnaire., Setting: Six Brazilian Reference Centres on gestational trophoblastic disease., Population: 2662 patients with MP/postmolar GTN treated from March-December/2015-2020 were retrospectively evaluated and 528 of these patients answered a questionnaire., Methods: Longitudinal retrospective multicentre study of patients diagnosed with MP/ postmolar GTN at presentation and a cross-sectional analysis, with application of a questionnaire, exclusive to patients treated during the period of study, to assess living and health conditions during the COVID-19 pandemic compared with previous years., Main Outcome Measures: The incidence of MP/postmolar GTN., Results: Compared with the last 5 pre-pandemic years, MP/postmolar GTN incidence remained stable during 2020 (COVID-19 pandemic). Multivariable logistic regression, adjusted for the patient age, showed that during 2020, presentation with MP was more likely to be >10 weeks of gestation (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.90-3.29, P < 0.001), have a pre-evacuation hCG level ≥100 000 iu/l (aOR 1.77, 95% CI 1.38-2.28, P < 0.001) and time to the initiation of chemotherapy ≥7 months (aOR 1.86, 95% CI 1.01-3.43, P = 0.047) when compared with 2015-2019., Conclusions: Although the incidence of MP/postmolar GTN remained stable during the COVID-19 pandemic in Brazil, the pandemic was associated with greater gestational age at MP diagnosis and more protracted delays in initiation of chemotherapy for postmolar GTN., (© 2022 John Wiley & Sons Ltd.)

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers' germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caporali, Fiorini, Palombo, Romagnoli, Baccari, Zenesini, Visconti, Posar, Scaduto, Ormanbekova, Battaglia, Tancredi, Cameli, Viggiano, Olivieri, Torroni, Maestrini, Rochat, Bacchelli, Carelli and Maresca.)

Objective: To assess perinatal outcomes of first pregnancy after remission from gestational trophoblastic neoplasia and the impact of the time between the end of chemotherapy and the subsequent pregnancy., Data Sources: The Medical Subject Headings related to perinatal outcomes, chemotherapy, and gestational trophoblastic neoplasia were used alone or in combination to retrieve relevant articles. We searched all references registered until April, 2019 in Embase, LILACS, MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science., Study Eligibility Criteria: We included any observational or interventional studies that evaluated perinatal outcomes of first pregnancy after chemotherapy for gestational trophoblastic neoplasia. Animal studies, narrative reviews, expert opinions, and previous treatments with potential risks for future perinatal outcomes which may introduce confounding bias were excluded., Study Appraisal and Synthesis Methods: Two reviewers independently screened all identified references for eligibility and data extraction. Methodological quality and bias of included studies were assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from the National Institutes of Health. For the meta-analysis, the measures of association were calculated using bivariate random-effects models. Statistical heterogeneity was evaluated with I 2 statistics and explored through sensitivity analysis. Publication bias was assessed by visual inspection of the funnel plot or Egger's test, according to the number of articles included. For all analyses, a P value of <.05 indicated statistical significance. This study was registered on PROSPERO (CRD42018116513)., Results: A total of 763 studies were identified after literature search and 23 original studies were included in the systematic review and in the meta-analysis. The combined data from the subgroup meta-analysis (outcome vs time after chemotherapy) showed an incidence of spontaneous abortion of 15.28% (95% confidence interval, 12.37-18.74; I 2 =73%), 3.30% of malformation (95% confidence interval, 2.27-4.79; I 2 =31%), 6.19% of prematurity (95% confidence interval, 5.03-7.59; I 2 =0), and 1.73% of stillbirth (95% confidence interval, 1.17-2.55; I 2 =0%). These results were not influenced by the time between the end of chemotherapy and the subsequent pregnancy in most of the studied outcomes, including malformation (P=.14, I 2 =31%), prematurity (P=.46, I 2 =0), and stillbirth (P=.66, I 2 =0). However, there was a higher occurrence of spontaneous abortion (P<.01, I 2 =73%) in pregnancies that occurred ≤6 months after chemotherapy., Conclusion: Chemotherapy for gestational trophoblastic neoplasia does not appear to increase the chance of unfavorable perinatal outcomes, except for the higher occurrence of spontaneous abortion in pregnancies occurring ≤6 months after chemotherapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Ca v ) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Ca v genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Ca v 3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Ca v 3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca 2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Viggiano, D'Andrea, Cameli, Posar, Visconti, Scaduto, Colucci, Rochat, Ceroni, Milazzo, Fucile, Maestrini and Bacchelli.)

Objectives: To compare ultrasound (US) and magnetic resonance imaging (MRI) in the assessment of mediastinal shift angles (MSAs) in fetuses affected by isolated left congenital diaphragmatic hernia (CDH). The use of MRI-MSA and US-MSA as prognostic factor for postnatal survival in fetal left CDH was also explored., Methods: This was an observational study of 29 fetuses with prenatally diagnosed isolated left CDH, assessed with both US and MRI examinations between January 2015 and December 2018. The US-MSA measurements performed within 2 weeks from the MRI assessment were considered for the analysis. The primary outcome was the postnatal survival rate., Results: No significant difference between US and MRI MSAs was detected ( p  = .419). Among the 29 cases, there were 21 alive infants, for an overall postnatal survival rate of 72.41%. After stratifying for postnatal survival, the best cutoffs with the highest discriminatory power in terms of sensibility and specificity were 42.1° for the US-MSA and 39.1° for the MRI-MSA. The performance of MRI-MSA in predicting postnatal survival was close to that of US-MSA in terms of sensitivity (62.5 versus 50.0%), specificity (80.9 versus 90.5%), positive predictive value (55.6 versus 66.7%), negative predictive value (85.0 versus 82.6%) and accuracy (75.9 versus 79.3%). There was no statistically significant difference between the two modalities ( p  > .05 for all)., Conclusions: MRI and US can be interchangeably used for the assessment of MSA in prenatally diagnosed isolated left CDH. Moreover, MSA measured by both US and MRI was confirmed to be correlated with perinatal outcome in terms of survival.