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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).)

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.

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.)

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.)

Neuroblastoma (NB) is one of the most frequently occurring neurogenic extracranial solid cancers in childhood and infancy. Over the years, many pieces of evidence suggested that NB development is controlled by gene expression dysregulation. These unleashed programs that outline NB cancer cells make them highly dependent on specific tuning of gene expression, which can act co-operatively to define the differentiation state, cell identity, and specialized functions. The peculiar regulation is mainly caused by genetic and epigenetic alterations, resulting in the dependency on a small set of key master transcriptional regulators as the convergence point of multiple signalling pathways. In this review, we provide a comprehensive blueprint of transcriptional regulation bearing NB initiation and progression, unveiling the complexity of novel oncogenic and tumour suppressive regulatory networks of this pathology. Furthermore, we underline the significance of multi-target therapies against these hallmarks, showing how novel approaches, together with chemotherapy, surgery, or radiotherapy, can have substantial antineoplastic effects, disrupting a wide variety of tumorigenic pathways through combinations of different treatments.

Background: Assisted reproductive technologies (ART) are becoming widespread, accounting for approximately 2% of all births in the western countries. Concerns exist on the potential association of ART with congenital anomalies. Few studies have addressed if a relationship exists between ART and the development of anorectal malformation (ARM). Our aim was to analyze the relationship between ARM and ART. Methods: Single-center retrospective case control study of all patients treated for ARM between 2010 and 2017. Patients with bronchiolitis treated since 2014 were used as controls. Variables analyzed include the following: prevalence of ART, gestational age, birth weight, and maternal age. Patients with ARM born after ART were also compared with those naturally conceived for disease complexity. Fisher's exact and Mann-Whitney U -tests were used as appropriate. Results: Three hundred sixty-nine patients were analyzed (143 cases and 226 controls). Prevalence of ART was significantly higher in ARM patients than in controls [7.6 vs. 3.0%; odds ratio: 2.59 (95% CI, 0.98-0.68); p = 0.05]. Among ARM patients, incidence of VACTERL association (17%) is more frequent in ART babies. Conclusion: Patients with ARM were more likely to be conceived following ART as compared with controls without congenital anomalies. Disease complexity of patients with ARM born after ART seems greater that those born after nonassisted conception., 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 © 2021 Iacusso, Iacobelli, Morini, Totonelli, Viggiano, Caforio and Bagolan.)

Aim of the study: Lymphatic malformations (LMs) are rare entities, sometimes difficult to treat, that may be life-threatening when intricately connected to airway structures. Invasive treatments are occasionally required, with sclerotherapy considered the treatment of choice and surgery as a second-line approach. The aim of the present study was to evaluate our multidisciplinary team experience in treating newborns affected by LMs requiring operative management, while defining early outcomes. Methods: Retrospective review of all consecutive patients admitted for LMs requiring operative management between January 2000 and January 2019. Patients were mainly characterized based on anatomical district of the LM (and further stratified based on the development of respiratory distress), need for tracheostomy, number of sclerotherapies, indication for surgery, and residual disease beyond the 1st year. Morbidity and mortality were also evaluated. Fisher exact test and Mann-Whitney test were used as appropriate. Statistical significance was set at p < 0.05. Results: Fifty-seven patients were included in the study, 36 with cervicofacial and/or mediastinal LMs and 21 with LMs of other anatomical districts. Due to the risk of developing respiratory distress at birth, patients with cervicofacial and/or mediastinal LMs were divided into two groups (8/36 group A vs. 28/36 group B). Group A patients are at higher risk for tracheostomy (7/8 group A vs. 1/28 group B, p = 0.0001) and more often require surgical reduction of the residual lymphatic abnormality (5/8 group A vs. 4/28 group B, p = 0.013). They also require sclerotherapies more often, but the difference is not statistically significant (8/8 group A vs. 19/28 group B, p = 0.15). Patients with cervicofacial/mediastinal LMs frequently suffer from persistent residual disease beyond the 1st year of life, significantly more often in group A (7/8 group A vs. 12/28 group B, p = 0.043). Conclusion: LMs are rare conditions with potential life-threatening behavior. Their intrinsic clinical complexity requires a multidisciplinary approach to the affected patients. Planning a long-term follow-up is essential because of the late-term problems those patients may experience., 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 © 2021 Scuglia, Conforti, Valfrè, Totonelli, Iacusso, Iacobelli, Meucci, Viggiano, Fusaro, Diociaiuti, Morini, El Hachem and Bagolan.)

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole-exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion-transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10 -5 ). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low-level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large-effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copy-number variants (CNVs) and protein-disrupting single-nucleotide variants (SNVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the Illumina PsychArray, to perform an integrated analysis of CNVs and SNVs and to assess their contribution to ASD risk. We observed a higher burden of rare CNVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare CNVs intersecting ASD candidate genes reported in the SFARI database. Family-based analysis of rare SNVs genotyped by the PsychArray also indicated an increased transmission of rare SNV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN, and RNF113A genes in ASD susceptibility. Finally, we showed that the PsychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb.

Background: The term gestational trophoblastic disease (GTD) includes both complete and partial moles, which are uncommon nonviable pregnancies with the potential to evolve into a malignancy known as gestational trophoblastic neoplasia. While highly curable, the potential for malignancy associated with molar pregnancies worries the patients, leading them to seek information on the internet. A Facebook page headed by Brazilian specialized physicians in GTD was created in 2013 to provide online support for GTD patients., Objective: The objective of our study was to describe the netnography of Brazilian patients with GTD on Facebook (FBGTD) and to evaluate whether their experiences differed depending on whether they received care in a Brazilian gestational trophoblastic disease reference center (BRC) or elsewhere., Methods: This was a cross-sectional study using G Suite Google Platform. The members of FBGTD were invited to participate in a survey from March 6 to October 5, 2017, and a netnographic analysis of interactions among the members was performed., Results: The survey was answered by 356 Brazilian GTD patients: 176 reference center patients (RCP) treated at a BRC and 180 nonreference center patients (NRCP) treated elsewhere. On comparing the groups, we found that RCP felt safer and more confident at the time of diagnosis of GTD (P=.001). RCP were more likely to utilize FBGTD subsequent to a referral by health assistants (P<.001), whereas NRCP more commonly discovered FBGTD through Web searches (P<.001). NRCP had higher educational levels (P=.009) and were more commonly on FBGTD for ≥ 6 months (P=.03). NRCP were more likely to report that doctors did not adequately explain GTD at diagnosis (P=.007), had more doubts about GTD treatment (P=.01), and were less likely to use hormonal contraception (P<.001). Overall, 89% (317/356) patients accessed the internet preferentially from home and using mobile phones, and 98% (349/354) patients declared that they felt safe reading the recommendations posted by FBGTD physicians., Conclusions: This netnographic analysis of GTD patients on FBGTD shows that an Web-based doctor-patient relationship can supplement the care for women with GTD. This resource is particularly valuable for women being cared for outside of established reference centers., (©Marisa Victoria Diniz, Sue Y Sun, Claudia Barsottini, Mauricio Viggiano, Roney C Signorini Filho, Bruna Sanches Ozane Pimenta, Kevin M Elias, Neil S Horowitz, Antonio Braga, Ross S Berkowitz. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 24.09.2018.)

The effect of the inhibition of nitric oxide synthase (NOS) on ovum transport and oviductal motility in rats was investigated. Three different NOS inhibitors were injected into the ovarian bursa at oestrus or day 3 of pregnancy. Oviducts and uteri were flushed 24 h later and the presence of ova was recorded. In oestrous and pregnant rats, treatment resulted in accelerated egg transport, as shown by a decrease in the number of ova present in the oviducts. In cyclic rats, intrabursal injection of 1 mg kg-1 of either N-monomethyl-L-arginine (L-NMMA) or N omega nitro-L-arginine methyl ester (L-NAME) elicited a 30% reduction in the number of ova present in the oviducts, whereas in pregnant animals, the same dose of L-NMMA produced a reduction of 40%. Simultaneous administration of the NO donor spermine NONOate (5 mg kg-1) completely reversed the effect of L-NMMA. Tubal motility was assessed by microsphere displacement analysis within the oviduct. Surrogate ova were transferred to the oviductal lumen at oestrus and 24 h later the effect of intraoviductal injection of 1 microgram L-NMMA or vehicle was assessed. The microspheres in the isthmus showed an oscillating motion, and periods in which movement was not detectable. However, L-NMMA treatment produced a 3.6-fold increase in the maximum instant velocities and a significant reduction in the resting periods of the microspheres compared with the control group (P < 0.001). These results provide evidence that NO inhibition increases tubal motility that results in accelerated ovum transport, and indicate that NO could act as a paracrine signal between different layers of the oviductal wall, providing a role for endogenous NO in regulation of tubal function.