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BACKGROUND: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE. METHODS: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models. RESULTS: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes. CONCLUSIONS: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.
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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. Setting: Fetal surgery was performed at a quaternary care center. Participants: A prospective cohort of patients referred for fetal spina bifida underwent fetoscopic repair under an FDA-approved protocol. Of 60 lesions repaired, 57 had available images and were included in the analysis. Interventions or Exposures: We evaluated lesion morphology on high-resolution intraoperative images and videos to categorize lesions based on placode exposure and nerve root stretching. Main Outcomes and Measures: The reproducibility of the lesion classification was assessed via Kappa interrater agreement. Preoperative characteristics analyzed include ventricle size, tonsillar herniation level, lower extremities movement, and lesion dimensions. Outcomes included surgical time, need for patch for skin closure, gestational age at delivery, preterm premature rupture of membranes (PPROM), and neonatal cerebrospinal fluid (CSF) diversion. Results: We distinguished five lesion types that differ across a range of sac sizes, nerve root stretching, and placode exposure, with 93% agreement between examiners (p<0.001). Fetal characteristics at preoperative evaluation differed significantly by lesion type, including lesion volume (p<0.001), largest ventricle size (p=0.008), tonsillar herniation (p=0.005), and head circumference (p=0.03). Lesion level, talipes, and lower extremities movement did not differ by type. Surgical and perinatal outcomes differed by lesion type, including need for patch skin closure (p<0.001), gestational age at delivery (p=0.01), and NICU length of stay (p<0.001). PPROM, CSF leakage at birth, and CSF diversion in the NICU did not differ between lesion groups. Linear regression associated severity of ventriculomegaly with lesion type, but not with tonsillar herniation level. Conclusions and Relevance: There is a distinct phenotypic spectrum in open spina bifida with differential baseline presentation and outcomes. Severity of ventriculomegaly is associated with lesion type, rather than tonsillar herniation level. Our findings expand the classification of spina bifida to reveal a spectrum that warrants further study.
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Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.
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Deleção Cromossômica , Cromossomos Humanos Par 22 , Meningomielocele , Animais , Feminino , Humanos , Masculino , Camundongos , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Sequenciamento do Exoma , Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Meningomielocele/epidemiologia , Meningomielocele/genética , Penetrância , Disrafismo Espinal/genética , Risco , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
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. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome-wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes.
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Epilepsia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esclerose Tuberosa , Humanos , Esclerose Tuberosa/genética , Esclerose Tuberosa/complicações , Epilepsia/genética , Epilepsia/epidemiologia , Feminino , Masculino , Adulto , Variação Genética , Genótipo , Adolescente , Fenótipo , Criança , Polimorfismo de Nucleotídeo Único , Pré-EscolarRESUMO
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. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination. CONCLUSIONS: Mutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.
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Proteínas do Domínio Armadillo , Defeitos do Tubo Neural , Disrafismo Espinal , Animais , Humanos , Camundongos , Proteínas do Domínio Armadillo/genética , Ácido Fólico/metabolismo , Camundongos Knockout , Mutação , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/epidemiologia , Disrafismo Espinal/genéticaRESUMO
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_000548.5(TSC2):c.4255_4256delCA, predicted to result in nonsense-mediated mRNA decay (NMD) and cessation of TSC2 protein production and thus pathogenic according to ACMG criteria, identified by NIPS and subsequently detected in family members with few or no symptoms of TSC. Due to the lack of TSC-associated features in the family, we hypothesized that the deletion created a non-canonical 5' donor site resulting in cryptic splicing and a transcript encoding active TSC2 protein. Verifying the predicted effect of the variant was key to designating pathogenicity in this case and should be considered for other frameshift variants in other genetic disorders. METHODS: Phenotypic information on the family members was collected via review of the medical records and patient reports. RNA studies were performed using proband mRNA isolated from blood lymphocytes for RT-PCR and Sanger sequencing. Functional studies were performed by transient expression of the TSC2 variant proteins in cultured cells, followed by immunoblotting. RESULTS: No family members harboring the variant met any major clinical diagnostic criteria for TSC, though a few minor features non-specific to TSC were present. RNA studies supported the hypothesis that the variant caused cryptic splicing, resulting in an mRNA transcript with an in-frame deletion of 93 base pairs r.[4255_4256del, 4251_4343del], p.[(Gln1419Valfs*104), (Gln1419_Ser1449del)]. Expression studies demonstrated that the canonical function of the resulting truncated TSC2 p.Gln1419_Ser1449del protein product was maintained and similar to wildtype. CONCLUSION: Although most frameshift variants are likely to result in NMD, the NM_000548.5(TSC2):c.4255_4256delCA variant creates a cryptic 5' splice donor site, resulting in an in-frame deletion that retains TSC2 function, explaining why carriers of the variant do not have typical features of TSC. The information is important for this family and others with the same variant. Equally important is the lesson that predictions can be inaccurate, and that caution should be used when designating frameshift variants as pathogenic, especially when phenotypic information to corroborate testing results is unavailable. Our work demonstrates that functional RNA- and protein-based confirmation of the effects of DNA variants improves molecular genetic diagnostics.
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Proteínas Supressoras de Tumor , Proteínas Supressoras de Tumor/genética , Mutação , Proteína 2 do Complexo Esclerose Tuberosa/genética , Virulência , Fenótipo , RNA MensageiroRESUMO
SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.
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Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Feminino , Masculino , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/complicações , Haploinsuficiência/genética , Deficiência Intelectual/patologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , HumanosRESUMO
Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.
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Exoma , Disrafismo Espinal , Animais , Modelos Animais de Doenças , Exoma/genética , Humanos , Camundongos , Disrafismo Espinal/genética , Sequenciamento do ExomaRESUMO
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 Snx3, a sorting nexin gene. Snx3-/- mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3-/- embryos and a defect in convergent extension of the neural epithelium. Snx3-/- cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance of SNX3 in WNT signaling regulation is demonstrated by rescue of NT closure in Snx3-/- embryos with a WNT agonist. The potential for SNX3 to function in human neurulation is revealed by a point mutation identified in an NTD-affected individual that results in functionally impaired SNX3 that does not colocalize with WLS and the degradation of WLS in the lysosome. These data indicate that Snx3 is crucial for NT closure via its role in recycling WLS in order to control levels of WNT signaling.
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Lisossomos/metabolismo , Defeitos do Tubo Neural/embriologia , Tubo Neural/embriologia , Receptores Acoplados a Proteínas G/metabolismo , Nexinas de Classificação/metabolismo , Via de Sinalização Wnt , Animais , Humanos , Lisossomos/genética , Lisossomos/patologia , Camundongos , Camundongos Knockout , Tubo Neural/patologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Receptores Acoplados a Proteínas G/genética , Nexinas de Classificação/genéticaRESUMO
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. The purpose of the study was to evaluate the combined risk prediction of previously identified risk factors for epilepsy in individuals with tuberous sclerosis complex. METHODS: The study group (n = 333) consisted of individuals with tuberous sclerosis complex who were enrolled in the Tuberous Sclerosis Complex Autism Center of Excellence Research Network and UT TSC Biobank. The outcome was defined as having an epilepsy diagnosis. Potential risk factors included sex, TSC genotype, and tuber presence. Logistic regression was used to calculate the odds ratio and P value for the association between each variable and epilepsy. A clinical risk prediction model incorporating all risk factors was built. Area under the curve was calculated to characterize the full model's ability to discriminate individuals with tuberous sclerosis complex with and without epilepsy. RESULTS: The strongest risk for epilepsy was presence of tubers (95% confidence interval: 2.39 to 10.89). Individuals with pathogenic TSC2 variants were three times more likely (95% confidence interval: 1.55 to 6.36) to develop seizures compared with those with tuberous sclerosis complex from other causes. The combination of risk factors resulted in an area under the curve 0.73. CONCLUSIONS: Simple characteristics of patients with tuberous sclerosis complex can be combined to successfully predict epilepsy risk. A risk assessment model that incorporates sex, TSC genotype, protective TSC2 missense variant, and tuber presence correctly predicts epilepsy in 73% of patients with tuberous sclerosis complex.
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Epilepsia/diagnóstico , Epilepsia/etiologia , Esclerose Tuberosa/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adulto JovemRESUMO
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. To compare mutational burden, we collapsed rare deleterious variants across each of 523 human WNT signaling genes in case and reference populations. Ten WNT signaling genes were disrupted with a higher mutational burden among Mexican American myelomeningocele subjects compared to reference subjects (Fishers exact test, P ≤ 0.05) and seven different genes were disrupted among individuals of European ancestry compared to reference subjects. Gene ontology enrichment analyses indicate that genes disrupted only in the Mexican American population play a role in planar cell polarity whereas genes identified in both populations are important for the regulation of canonical WNT signaling. In summary, evidence for WNT signaling genes that may contribute to myelomeningocele in humans is presented and discussed.
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Meningomielocele/genética , Mutação , Via de Sinalização Wnt , Polaridade Celular , Ontologia Genética , Humanos , Taxa de Mutação , Proteínas Wnt/genéticaRESUMO
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. METHODS: Exome sequencing (ES) was performed in 511 patients, born with myelomeningocele, divided between European American and Mexican American ethnicities. Healthy control data from the Genome Aggregation database were ethnically matched and used as controls. Rare, high fidelity, nonsynonymous predicted damaging missense, nonsense, or canonical splice site variants in independently generated candidate gene lists for FOCM and GHOS were identified. We used a gene-based collapsing approach to quantify mutational burden in case and controls, with the control cohort estimated using cumulative allele frequencies assuming Hardy-Weinberg equilibrium. RESULTS: We identified 45 of 837 genes in the FOCM network and 22 of 568 genes in the GHOS network as possible NTD risk genes with p < 0.05. No nominally significant risk genes were shared between ethnicities. Using a novel approach to mutational burden we identify 55 novel NTD risk associations. CONCLUSIONS: We provide a means of utilizing large publicly available sequencing datasets as controls for sequencing projects examining rare disease. This approach confirmed existing risk genes for myelomeningocele and identified possible novel risk genes. Lastly, it suggests possible distinct genetic etiologies for this malformation between different ethnicities.
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Redes Reguladoras de Genes , Meningomielocele/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Exoma , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Estresse OxidativoRESUMO
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. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. METHODS: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. RESULTS: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. CONCLUSIONS: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.
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Deficiências do Desenvolvimento , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa , Pré-Escolar , Cognição/fisiologia , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Genótipo , Humanos , Desenvolvimento da Linguagem , Aprendizagem/fisiologia , Masculino , Fenótipo , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/fisiopatologiaRESUMO
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. We consider genotype-phenotype correlations as an example of precision medicine, and discuss genetic counseling in TSC, with the aim of providing geneticists and health care practitioners involved in the care of TSC individuals with useful tools for their practice.
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Aconselhamento Genético , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/etiologia , Estudos de Associação Genética , Testes Genéticos , Humanos , Mosaicismo , Mutação , Linhagem , Medicina de Precisão , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Esclerose Tuberosa/genéticaRESUMO
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. METHODS: Two multicenter, prospective studies enrolled 130 infants with definite TSC by clinical or genetic criteria and followed them longitudinally up to 36 months of age. Periodic study visits included medical and seizure histories, physical and neurologic examinations, and developmental assessments. Ages at which major and minor features of TSC and seizures were first identified were analyzed. RESULTS: The most common initial presenting features of TSC were cardiac rhabdomyomas (59%) and hypomelanotic macules or other skin findings (39%), and 85% of infants presented with either or both. Ultimately, the most prevalent diagnostic TSC features were hypomelanotic macules (94%), tubers or other cortical dysplasias (94%), subependymal nodules (90%), and cardiac rhabdomyomas (82%). Thirty-five percent of infants presented prenatally, 41% presented at birth or within the first month of life, and 74% met criteria for TSC diagnosis at or within 30 days of presentation. Seizure onset occurred before or at initial presentation in only 15% of infants, but 73% developed epilepsy within the first year of life. CONCLUSIONS: Infants with TSC can often be identified early, before the onset of neurologic sequelae, enabling earlier diagnosis, surveillance, and possibly disease-modifying treatment.
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Esclerose Tuberosa/diagnóstico , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Prevalência , Estudos ProspectivosRESUMO
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 3-6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35-50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.
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Deficiência de Ácido Fólico/epidemiologia , Ácido Fólico/genética , Defeitos do Tubo Neural/epidemiologia , Feminino , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/patologia , Humanos , Tubo Neural/crescimento & desenvolvimento , Tubo Neural/metabolismo , Tubo Neural/patologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Gravidez , Fatores Socioeconômicos , Estados UnidosRESUMO
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. This study examines whether variants within the folate transporter and receptor genes are associated with an increased risk for myelomeningocele (MM). Exons and their flanking intron sequences of 348 MM subjects were sequenced using the Sanger sequencing method and/or next generation sequencing to identify variants. Frequencies of alleles of single nucleotide polymorphisms (SNPs) in MM subjects were compared to those from ethnically matched reference populations to evaluate alleles' associated risk for MM. We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1, FOLR2, and FOLR3. Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3, and a stop_gain variant in FOLR3. No new variants were identified in SLC46A1, SLC25A32, or FOLH1. In SLC19A1, c.80A>G (rs1051266) was not associated with our MM cohort; we did observe a variant allele G frequency of 61.7%, higher than previously reported in other NTD populations. In conclusion, we discovered novel loss of function variants in genes involved in folate transport in MM subjects. Our results support the growing evidence of associations between genes involved in folate transport and susceptibility to NTDs.
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Proteínas de Transporte/genética , Receptor 1 de Folato/genética , Receptor 2 de Folato/genética , Meningomielocele/genética , Proteína Carregadora de Folato Reduzido/genética , Alelos , Éxons/genética , Feminino , Ácido Fólico/genética , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Humanos , Masculino , Meningomielocele/fisiopatologia , Mutação , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
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. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.
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Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Carcinoma/genética , Carcinoma/metabolismo , Genômica , Humanos , Mutação , Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
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. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.
Assuntos
Alelos , Estudos de Associação Genética , Mutação , Fenótipo , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Substituição de Aminoácidos , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Linhagem , Rabdomioma/diagnóstico , Rabdomioma/genética , Rabdomioma/cirurgia , Índice de Gravidade de Doença , Proteína 2 do Complexo Esclerose TuberosaRESUMO
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. A dietary questionnaire was used to obtain information on maternal dietary intake on eight micronutrients including folate and cobalamin. TaqMan assays were used to generate MTHFR C677T and A1298C genotypes. Log-linear models were used to evaluate the joint effects of maternal genotype and micronutrient intake dichotomized as at or above versus below the United States Recommended Dietary Allowance (US RDA) on MM. RESULTS: There was little evidence to suggest maternal MTHFR genotypes interacted with micronutrient intake to influence the risk of MM. For instance, the effect of MTHFR 677T was similar for mothers with cobalamin intake below US RDA (relative risk [RR] = 0.97) versus at or above US RDA cobalamin intake (RR = 0.81, interaction p = 0.87). However, some differences were noted. For example, the effect of MTHFR 1298C appeared to be different between those mothers below US RDA folate intake (RR = 0.98) versus those at or above US RDA folate intake (RR = 0.68), but the interaction was not statistically significant (interaction p = 0.27). CONCLUSION: There did not appear to be strong effects of maternal micronutrient intake on the role of maternal genetic polymorphisms in MTHFR C677T and A1298C on MM risk. Birth Defects Research 109:99-105, 2017. © 2016 Wiley Periodicals, Inc.