Morphometric Analysis of Spina Bifida after Fetal Repair Shows New Subtypes with Associated Outcomes.

Importance: The binary classification of spina bifida lesions as myelomeningocele (with sac) or myeloschisis (without sac) belies a spectrum of morphologies, which have not been correlated to clinical characteristics and outcomes.

Objective: To characterize spina bifida lesion types and correlate them with preoperative presentation and postoperative outcomes.

Design: Secondary analysis of images and videos obtained during fetoscopic spina bifida repair surgery from 2020-2023.

Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex.

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population.

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans.

Background: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II).

Results: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly.

Mild TSC phenotype and non-penetrance associated with a frameshift variant in TSC2 prompts caution in evaluating pathogenicity of frameshift variants.

Introduction: Technological advances in genetic testing, particularly the adoption of noninvasive prenatal screening (NIPS) for single gene disorders such as tuberous sclerosis complex (TSC, OMIM# 613254), mean that putative/possible pathogenetic DNA variants can be identified prior to the appearance of a disease phenotype. Without a phenotype, accurate prediction of variant pathogenicity is crucial. Here, we report a TSC2 frameshift variant, NM_000548.

is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling.

Disruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of , a sorting nexin gene. mutant mouse embryos display a fully-penetrant cranial NTD.

Epilepsy Risk Prediction Model for Patients With Tuberous Sclerosis Complex.

Background: Individuals with tuberous sclerosis complex are at increased risk of epilepsy. Early seizure control improves developmental outcomes, making identifying at-risk patients critically important. Despite several identified risk factors, it remains difficult to predict.

Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients.

Genes in the noncanonical WNT signaling pathway controlling planar cell polarity have been linked to the neural tube defect myelomeningocele. We hypothesized that some genes in the WNT signaling network have a higher mutational burden in myelomeningocele subjects than in reference subjects in gnomAD. Exome sequencing data from 511 myelomeningocele subjects was obtained in-house and data from 29,940 ethnically matched subjects was provided by version 2 of the publicly available Genome Aggregation Database.

Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one-carbon metabolism networks.

Background: Neural tube defects (NTDs) are the second most common complex birth defect, yet, our understanding of the genetic contribution to their development remains incomplete. Two environmental factors associated with NTDs are Folate and One Carbon Metabolism (FOCM) and Glucose Homeostasis and Oxidative Stress (GHOS). Utilizing next-generation sequencing of a large patient cohort, we identify novel candidate genes in these two networks to provide insights into NTD mechanisms.

Tuberous Sclerosis Complex Genotypes and Developmental Phenotype.

Background: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied.

Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice.

Tuberous Sclerosis Complex (TSC) is a multisystem autosomal dominant condition caused by inactivating pathogenic variants in either the TSC1 or the TSC2 gene, leading to hyperactivation of the mTOR pathway. Here, we present an update on the genetic and genomic aspects of TSC, with a focus on clinical and laboratory practice. We briefly summarize the structure of TSC1 and TSC2 as well as their protein products, and discuss current diagnostic testing, addressing mosaicism.

Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants.

Objectives: Tuberous sclerosis complex (TSC) is a neurocutaneous genetic disorder with a high prevalence of epilepsy and neurodevelopmental disorders. TSC can be challenging to diagnose in infants because they often do not show many clinical signs early in life. In this study, we describe the timing and pattern of presenting and diagnostic features in a prospective longitudinal study of infants with TSC.

Mutations in folate transporter genes and risk for human myelomeningocele.

The molecular mechanisms linking folate deficiency and neural tube defect (NTD) risk in offspring remain unclear. Folate transporters (SLC19A1, SLC46A1, SLC25A32, and FOLH1) and folate receptors (FOLR1, FOLR2, and FOLR3) are suggested to play essential roles in transporting folate from maternal intestinal lumen to the developing embryo. Loss of function variants in these genes may affect folate availability and contribute to NTD risk.

Finding the genetic mechanisms of folate deficiency and neural tube defects-Leaving no stone unturned.

Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 to 200 per 10,000 births with the United States of American NTD incidence at around 3-6.

The genomic landscape of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants.

Genetic association of the glycine cleavage system genes and myelomeningocele.

Background: Neural tube defects (NTDs) are one of the most common congenital birth defects, with myelomeningocele (MM) being the most severe form compatible with life. Recent studies show a link between mitochondrial folate one carbon metabolism and NTDs by means of the glycine cleavage system (GCS). We hypothesize that single nucleotide polymorphisms and novel variants in the coding regions of the GCS genes increase the risk for MM.

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors.

Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors.

Maternal gene-micronutrient interactions related to one-carbon metabolism and the risk of myelomeningocele among offspring.

Background: Few studies have evaluated interactions between maternal genetic variation in 5,10-methylenetetrahydrofolate reductase (MTHFR) and micronutrient intake on the risk of myelomeningocele (MM) in offspring. Therefore, we sought to determine if the role of maternal MTHFR C677T and A1298C on MM risk is altered by maternal intake of micronutrients related to one-carbon metabolism.

Methods: The study consisted of 220 MM case-parent trios recruited from 1996 to 2006.

Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants.

Background: We assessed the clinical utility of routine electroencephalography (EEG) in the prediction of epilepsy onset in asymptomatic infants with tuberous sclerosis complex.

Methods: This multicenter prospective observational study recruited infants younger than 7 months, seizure-free and on no antiepileptic drugs at enrollment, who all underwent serial physical examinations and video EEGs throughout the study. Parental education on seizure recognition was completed at the time of initial enrollment.

Association of facilitated glucose transporter 2 gene variants with the myelomeningocele phenotype.

Background: Neural tube defects (NTDs) remain the second most common cause of congenital malformations. Myelomeningocele (MM), the most common NTD compatible with survival, results from genetic and environmental factors. Epidemiologic studies and murine models support the hypotheses that obesity, diabetes and hyperglycemia confer increased risk of NTDs.