Optical Genome Mapping data from a Cohort of Neural Tube Defect Patients
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ABSTRACT:
ORGANISM(S): Homo sapiens (human)
SUBMITTER:
PROVIDER: S-BSST1664 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-02-25 | GSE167456 | GEO
Project description:Neural tube defects (NTDs) are severe malformations of the central nervous system that affect 1-2 individuals per 2,000 births. Their etiology is complex and involves both genetic and environmental factors. Our recent discovery that simultaneous removal of Cldn3, -4, and -8 from tight junctions results in cranial and spinal NTDs in both chick and mouse embryos suggests that claudins play a conserved role in neural tube closure in vertebrates. To determine if claudins were associated with NTDs in humans, we used a Fluidigm next generation sequencing approach to identify genetic variants in CLDN loci in 152 patients with spinal NTDs. We identified eleven rare and four novel missense mutations in ten CLDN genes. In vivo validation of variant pathogenicity using a chick embryo model system revealed that overexpression of four variants caused a significant increase in NTDs: CLDN3 A128T, CLDN8 P216L, CLDN19 I22T, and E209G. Our data implicate rare missense variants in CLDN genes as risk factors for spinal NTDs and suggest a new family of proteins involved in the pathogenesis of these malformations.
| S-EPMC7372130 | biostudies-literature
Project description:ObjectivesThe Neural Tube Defects Research Group of University of Malaya was approached to analyze a tablet named TELSE, which may have resulted in a baby born with central nervous system malformation at the University of Malaya Medical Centre. In this animal experimental study, we investigated the content of TELSE and exposure of its contents that resulted in failure of primary neurulation.ResultsLiquid Chromatography Tandem Mass spectrophotometry analysis of the TELSE tablet confirmed the presence of trimethoprim as the active compound. The TELSE tablet-treated females produced significant numbers of embryos with exencephaly (n = 8, 36.4%, *P < 0.0001), in all litters. The TELSE tablet-treated females subsequently given folic acid did not result in pregnancies despite there being evidence of possible resorption. Furthermore, after multiple rounds of mating which did not yield viable pregnancies, eventually, 2 embryos with exencephaly were harvested in a litter of 6 at 0.05% w/v pure trimethoprim once. The use of trimethoprim, a folic acid antagonist, peri-conceptionally increased the risk of exencephaly in the mouse.
| S-EPMC6048906 | biostudies-literature
Project description:Neural tube defects (NTDs), which include spina bifida and anencephaly, are the second most common form of human structural congenital malformations. While it is well established that SHROOM3 plays a pivotal role in the complex morphogenetic processes involved in neural tube closure (NTC), the underlying genetic contributions of SHROOM gene family members in the etiology of human NTDs remain poorly understood. Herein, we systematically investigated the mutation patterns of SHROOM1-4 in a Chinese population composed of 343 NTD cases and 206 controls, using targeted next-generation sequencing. Functional variants were further confirmed by western blot and the mammalian two-hybrid assays. Loss of function (LoF) variants were identified in SHROOM3. We observed 1.56 times as many rare [minor allele frequency (MAF) < 0.01] coding variants (p = 2.9 × 10-3) in SHROOM genes, and 4.5 times as many rare D-Mis (deleterious missense) variants in SHROOM2 genes in the NTD cases compared with the controls. D-Mis variants of SHROOM2 (p.A1331S; p.R1557H) were confirmed by Sanger sequencing, and these variants were determined to have profound effects on gene function that disrupted their binding with ROCK1 in vitro. These findings provide genetic and molecular insights into the effects of rare damaging variants in SHROOM2, indicating that such variants of SHROOM2 might contribute to the risk of human NTDs. This research enhances our understanding of the genetic contribution of the SHROOM gene family to the etiology of human NTDs.
| S-EPMC5876139 | biostudies-literature
Project description:Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of <0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.
| S-EPMC5966321 | biostudies-literature
Project description:BACKGROUND:Maternal diabetes during pregnancy is a well-known teratogen that increases the risk for birth defects, such as neural tube defects (NTDs). We have previously shown that maternal diabetes profoundly affects gene expression in the developing embryo, in particular a suite of known NTD genes. In rodent experimental systems, NTDs present as phenotypes of incomplete penetrance in diabetic pregnancies. This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos. RESULTS:Altered gene expression and increased variability of gene expression together may constitute the molecular correlates for incomplete phenotype penetrance. DISCUSSION:Based on this model, we suggest that maternal diabetes reduces the precision of gene regulation in exposed individuals. Loss of precision in embryonic gene regulation may include changes to the epigenome via deregulated expression of chromatin-modifying factors. Unraveling the mechanisms underlying such epigenetic modifications in diabetic pregnancies will help to understand how teratogenic insults compromise embryonic development and possibly provide avenues for therapeutic intervention.
| S-EPMC3509193 | biostudies-literature
Project description:BackgroundThe ostrich (Struthio camelus) is the tallest and heaviest living bird. Ostrich meat is considered a healthy red meat, with an annual worldwide production ranging from 12,000 to 15,000 tons. As part of the avian phylogenomics project, we sequenced the ostrich genome for phylogenetic and comparative genomics analyses. The initial Illumina-based assembly of this genome had a scaffold N50 of 3.59 Mb and a total size of 1.23 Gb. Since longer scaffolds are critical for many genomic analyses, particularly for chromosome-level comparative analysis, we generated optical mapping (OM) data to obtain an improved assembly. The OM technique is a non-PCR-based method to generate genome-wide restriction enzyme maps, which improves the quality of de novo genome assembly.FindingsIn order to generate OM data, we digested the ostrich genome with KpnI, which yielded 1.99 million DNA molecules (>250 kb) and covered the genome at least 500×. The pattern of molecules was subsequently assembled to align with the Illumina-based assembly to achieve sequence extension. This resulted in an OM assembly with a scaffold N50 of 17.71 Mb, which is 5 times as large as that of the initial assembly. The number of scaffolds covering 90% of the genome was reduced from 414 to 75, which means an average of ~3 super-scaffolds for each chromosome. Upon integrating the OM data with previously published FISH (fluorescence in situ hybridization) markers, we recovered the full PAR (pseudoatosomal region) on the ostrich Z chromosome with 4 super-scaffolds, as well as most of the degenerated regions.ConclusionsThe OM data significantly improved the assembled scaffolds of the ostrich genome and facilitated chromosome evolution studies in birds. Similar strategies can be applied to other genome sequencing projects to obtain better assemblies.
| S-EPMC4427950 | biostudies-literature
Project description:In polygenic disorders we do not know exactly, how many genes are involved in the pathomechanism, but the analysis of fetal gene expression can get us closer to the solution. In our study we were searching for the genetic background of the polygenic neural tube defect, which is the second most common birth defect in the world (1 in 1000 live births). Our data revealed novel candidate genes, like SLAP, LST1 and BENE, which can play an important role in the pathogenesis of neural tube defects. We created a data warehouse from the results, suitable for further analysis. This study also demonstrates that a routinely collected amount of amniotic fluid (as small as 6 mL) is enough to successfully hybridize isolated RNA to expression arrays, making the ability to use the technique from normally collected amniotic fluid samples. Keywords: Prenatal gene expression signature
2006-11-02 | GSE4182 | GEO
Project description:Rubinstein-Taybi syndrome (RSTS) is a rare dominant disorder with intellectual disability, postnatal growth deficiency, and multiple congenital anomalies. Approximately 50-70% of the patients have a mutation in the CREBBP gene (RSTS1) and 5-10% display an EP300 gene mutation (RSTS2). Craniospinal abnormalities such as microcranium, scoliosis, and lordosis are frequent findings in RSTS1, but malformations of the brain or spinal cord are seen only occasionally. Here, we report on a 3-year-old boy with facial abnormalities of RSTS, broad thumbs and halluces, developmental delay, autistic features, cerebellar underdevelopment, and a neural tube defect. Molecular diagnostic of the CREBBP and EP300 genes showed a heterozygous 17-bp deletion (c.5698_5714del AAGGCAGCAGGCCAGGT) in exon 31 of the EP300 gene. Findings underline that small (hypoplastic) cerebellum and neural tube defects belong to the phenotypic spectrum not only of RSTS1 but also of RSTS2. Based on the literature and this observation, we recommend that each individual with RSTS2 should be closely evaluated for neural axis and craniovertebral junction anomalies, and where appropriate, neuroimaging studies should be considered. Our frequency estimate of ~ 6% occult or overt neural tube defects in RSTS2 could represent an underestimate.
| S-EPMC6553355 | biostudies-literature