Impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in patients with Ebstein anomaly and tricuspid valve dysplasia

Objectives: To evaluate the impact of fetal haemodynamics on surgical and neurodevelopmental outcomes in severe Ebstein anomaly and tricuspid valve dysplasia. Methods: Thirty-four fetuses with Ebstein anomaly/tricuspid valve dysplasia were referred from 2013 to 2019 for fetal echocardiography and clinical management. Nineteen fetuses with Ebstein anomaly/tricuspid valve dysplasia and 30 controls underwent cardiovascular magnetic resonance to quantify the fetal blood flow and to calculate cerebral oxygen delivery (cDO2) and consumption (cVO2). The 3D steady-state free precession acquisition was used to measure fetal brain volume. Surgical outcome, brain MRI, and neurodevelopmental follow-up were reviewed. Results: Twenty-six fetuses were live born (76%) and survival (65%) at a mean follow-up of 4 years. Nine fetuses had a brain MRI before discharge, and all had clinically silent injuries and volume loss. At 18 months, five single-ventricle patients had a neurodevelopmental delay in cognition and language (mean percentile: 11th), with gross-motor skills more affected than fine-motor skills (mean percentiles: 4th and 34th). Fetuses with Ebstein anomaly/tricuspid valve dysplasia had smaller brains, lower combined ventricular output, ascending aorta, superior caval vien and umbilical vein flows, lower oxygen saturation in ascending aorta and superior caval vien, lower cDO2 and cVO2 (p < 0.05). Superior caval vien/combined ventricular output and descending aorta/combined ventricular output ratios were lower in fetuses with circular shunt (p < 0.05). Fetuses requiring the Starnes procedure tended to have smaller brains, lower combined ventricular output, superior caval vien, descending aorta, and umbilical vein flows. Conclusions: All patients with Ebstein anomaly/tricuspid valve dysplasia are at high risk of neurodevelopmental delay and warrant follow-up. Fetal cardiovascular magnetic resonance revealed impaired brain growth with diminished cerebral blood flow and cDO2, the extenting dependent on the severity of the haemodynamic compromise.

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype–phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Phenotypes in Children With SYNGAP1 Encephalopathy in China

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G &gt; A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.

Early aEEG can predict neurodevelopmental outcomes at 12 to 18 month of age in VLBWI with necrotizing enterocolitis: a cohort study

Background Studies have shown that neurological damage is common in necrotizing enterocolitis (NEC) survivors. The purpose of the study was to investigate the predictive value of amplitude-integrated electroencephalogram (aEEG) for neurodevelopmental outcomes in preterm infants with NEC. Methods Infants with NEC were selected, and the control group was selected based on 1:1–2 pairing by gestational age. We performed single-channel (P3–P4) aEEG in the two groups. The Burdjalov scores were compared between the two groups. Cranial magnetic resonance imaging (MRI) was performed several months after birth. The neurological outcomes at 12 to 18 months of age were compared with the Gesell Developmental Schedules (GDS). The predictive value of aEEG scores for neurodevelopmental delay was calculated. Results There was good consistency between the two groups regarding general conditions. In the 1st aEEG examination, the patients in NEC group had lower Co (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P = 0.001), Cy (1.0 (0.0, 2.0) vs. 3.0 (3.0, 4.0), P < 0.001), LB (1.0 (0.0, 2.0) vs. 2.0 (2.0, 2.0), P < 0.001), B (1.0 (1.0, 2.0) vs. 3.0 (3.0, 3.5), P < 0.001) and T (3.0 (2.0, 8.0) vs. 10.0 (10.0, 11.5), P < 0.001), than the control group. Cranial MRI in NEC group revealed a widened interparenchymal space with decreased myelination. The abnormality rate of cranial MRI in the NEC group was higher than that in the control group (P = 0.001). The GDS assessment indicated that NEC children had inferior performance and lower mean scores than the control group in the subdomains of gross motor (71 (SD = 6.41) vs. 92 (SD = 11.37), P < 0.001), fine motor (67 (SD = 9.34) vs. 96 (SD = 13.69), adaptive behavior (76 (SD = 9.85) vs. 95 (SD = 14.38), P = 0.001), language (68 (SD = 12.65) vs. 95 (SD = 11.41), P < 0.001), personal-social responses (80 (SD = 15.15) vs. 93(SD = 14.75), P = 0.037) and in overall DQ (72 (SD = 8.66) vs. 95 (SD = 11.07), P < 0.001). The logistic binary regression analysis revealed that the NEC patients had a significantly greater risk of neurodevelopmental delay than the control group (aOR = 27.00, 95% CI = 2.561–284.696, P = 0.006). Confirmed by Spearman’s rank correlation analysis, neurodevelopmental outcomes were significantly predicted by the 1st aEEG Burdjalov score (r = 0.603, P = 0.001). An abnormal 1st Burdjalov score has predictive value for neurodevelopmental delay with high specificity (84.62%) and positive predictive value (80.00%). Conclusions Children with NEC are more likely to develop neurodevelopmental delay. There is high specificity and PPV of early aEEG in predicting neurodevelopmental delay.