scholarly journals Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2014
Author(s):  
Mateusz Dawidziuk ◽  
Tomasz Gambin ◽  
Ewelina Bukowska-Olech ◽  
Dorota Antczak-Marach ◽  
Magdalena Badura-Stronka ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Molecular Basis ◽  
Biological Processes ◽  
High Confidence ◽  
Number Of Patients ◽  
Novel Variants ◽  
Clinical Diagnoses ◽  
Genetic Landscape ◽  
Congenital Microcephaly ◽  
Etiological Heterogeneity

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals Transcriptome analysis for the restrained stem development of the wheat mutant dms

2017 ◽  
Vol 47 (12) ◽  
Author(s):  
Ruishi He ◽  
Xinxin Zhu ◽  
Qiaoyun Li ◽  
Yumei Jiang ◽  
Dongyan Yu ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Expression Profiles ◽  
Triticum Aestivum L ◽  
Sequencing Analysis ◽  
Biological Processes ◽  
Causal Factors ◽  
Qrt Pcr ◽  
Stem Development ◽  
Wheat Mutant ◽  
Phytohormone Signaling

ABSTRACT: Wheat (Triticum aestivum L.) stem development significantly affects grain yield. The dwarf plants (D) of wheat mutant dms was less than 30cm. Here, we were to explore the molecular basis for the restrained stem development of the dwarf plants. The results were reached by compare the young spikes and stems transcriptomes of the tall (T) and D plants of mutant dms. We identified 663 genes highly expressed in stem tips. We identified 997 differentially expressed genes (DEGs) in stem tips between T and D, 403 DEGs were significantly related with stem development. Most biological processes in stem tips on dwarf plants were significantly suppressed, such as phytohormone signaling etc. The sequencing analysis results were confirmed by quantitatively analysis the expression profiles of fourteen key DEGs via real-time QRT-PCR. We identified a group genes related to wheat stem development, identified a group DEGs related to the restrained stem development of D plants of dms. The suppressed phytohormone signaling, carbohydrate transport and metabolism were the major causal factors leading to dwarf plants of D. Our dataset provides a useful resource for investigating wheat stem development.

scholarly journals Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

2021 ◽  
Vol 14 ◽  
Author(s):  
Chun Hu ◽  
Pan Feng ◽  
Qian Yang ◽  
Lin Xiao
Keyword(s):  
Neurodevelopmental Disorders ◽  
Basic Research ◽  
Genetic Data ◽  
Review Article ◽  
Biological Processes ◽  
Behavioral Impairment ◽  
Clinical Investigations ◽  
Substantial Progress ◽  
Biochemical Analyses ◽  
Made In

Despite the complexity of neurodevelopmental disorders (NDDs), from their genotype to phenotype, in the last few decades substantial progress has been made in understanding their pathophysiology. Recent accumulating evidence shows the relevance of genetic variants in thousand and one (TAO) kinases as major contributors to several NDDs. Although it is well-known that TAO kinases are a highly conserved family of STE20 kinase and play important roles in multiple biological processes, the emerging roles of TAO kinases in neurodevelopment and NDDs have yet to be intensively discussed. In this review article, we summarize the potential roles of the TAO kinases based on structural and biochemical analyses, present the genetic data from clinical investigations, and assess the mechanistic link between the mutations of TAO kinases, neuropathology, and behavioral impairment in NDDs. We then offer potential perspectives from basic research to clinical therapies, which may contribute to fully understanding how TAO kinases are involved in NDDs.

scholarly journals Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses

2019 ◽  
Author(s):  
Jihyung Lee ◽  
Junyan Zhang ◽  
Young-Jun Chung ◽  
Jun Hwan Kim ◽  
Chae Min Kook ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Dendritic Cells ◽  
Molecular Basis ◽  
Camp Signaling ◽  
Biological Processes ◽  
The Novel ◽  
Microbial Product ◽  
Conventional Type ◽  
Recognition Receptor

AbstractCyclic AMP (cAMP) is involved in multiple biological processes. However, little is known about its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent) regulates conventional type-2 Dendritic Cells (cDC2s), but not cDC1s and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors (TFs) for Th2 induction. Genetic loss of IRF4 phenocopies the effects of cAMP signaling on Th17-induction, indicating that the cAMP effect is secondary to repression of IRF4. Moreover, signaling in cDC2s by a PRR-dependent microbial product, curdlan, represses IRF4 and KLF4, resulting in a pro-Th17 phenotype. These results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the novel cDC2 and cDC17 classification. In addition, the data reveal that cAMP signaling can alter DCs function and fate by repressing IRF4 and KLF4, a pathway that can be harnessed for immuno-regulation.

scholarly journals Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

2018 ◽  
Author(s):  
Youngha Lee ◽  
Jin Sook Lee ◽  
Soo Yeon Kim ◽  
Jaeso Cho ◽  
Yongjin Yoo ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Neurodevelopmental Disorders ◽  
Pediatric Patients ◽  
Medical System ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants

AbstractImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).ObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.Design, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Children’s Hospital.ExposuresWES of patients and parents and subsequent evaluation of genetic variants.Main outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.ResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.Conclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.Key pointsQuestionWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?FindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.MeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

scholarly journals Cryo-EM reveals unique structural features of the FhuCDB Escherichia coli ferrichrome importer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Wenxin Hu ◽  
Hongjin Zheng
Keyword(s):  
Electron Microscopy ◽  
Escherichia Coli ◽  
Molecular Basis ◽  
Iron Uptake ◽  
Structural Features ◽  
Biological Processes ◽  
Type Ii ◽  
Functional Studies ◽  
Cryo Electron Microscopy ◽  
Translocation Pathway

AbstractAs one of the most elegant biological processes developed in bacteria, the siderophore-mediated iron uptake demands the action of specific ATP-binding cassette (ABC) importers. Although extensive studies have been done on various ABC importers, the molecular basis of these iron-chelated-siderophore importers are still not fully understood. Here, we report the structure of a ferrichrome importer FhuCDB from Escherichia coli at 3.4 Å resolution determined by cryo electron microscopy. The structure revealed a monomeric membrane subunit of FhuB with a substrate translocation pathway in the middle. In the pathway, there were unique arrangements of residues, especially layers of methionines. Important residues found in the structure were interrogated by mutagenesis and functional studies. Surprisingly, the importer’s ATPase activity was decreased upon FhuD binding, which deviated from the current understanding about bacterial ABC importers. In summary, to the best of our knowledge, these studies not only reveal a new structural twist in the type II ABC importer subfamily, but also provide biological insights in the transport of iron-chelated siderophores.

scholarly journals Pharmacogene sequencing of a Gabonese population with severe Plasmodium falciparum malaria reveals multiple novel variants with putative relevance for antimalarial treatment

2021 ◽  
Author(s):  
Leyre Pernaute-Lau ◽  
Ayola Akim Adegnika ◽  
Yitian Zhou ◽  
Jeannot F Zinsou ◽  
Jose Pedro Gil ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Disposition ◽  
Plasmodium Falciparum Malaria ◽  
Antimalarial Treatment ◽  
Increased Risk ◽  
Novel Variants ◽  
Genetic Landscape ◽  
Host Genetic ◽  
Genetic Profiles ◽  
Reduced Activity

Malaria remains one of the most deadly diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs). Host genetic variation in genes involved in drug disposition or toxicity constitutes an important determinant of ADR risk and can prime for parasite drug resistance. Importantly however, the genetic diversity in Africa is substantial and thus genetic profiles in one population cannot be reliably extrapolated to other ethnogeographic groups. Gabon is considered a high-transmission country with more than 460,000 malaria cases per year. Yet, the pharmacogenetic landscape of the Gabonese population or its neighboring countries has not been analyzed. Using targeted sequencing, we here profiled 21 pharmacogenes with importance for antimalarial treatment in 48 Gabonese pediatric patients with severe Plasmodium falciparum malaria. Overall, we identified 347 genetic variants of which 18 were novel and each individual was found to carry 87.3±9.2 SD variants across all analyzed genes. Importantly, 16.7% of these variants were population-specific, highlighting the need for high-resolution pharmacogenomic profiling. Between one in three and one in six individuals harbored reduced activity alleles of CYP2A6, CYP2B6, CYP2D6 and CYP2C8 with important implications for artemisinin, chloroquine and amodiaquine therapy. Furthermore, one in three patients harbored at least one G6PD deficient allele, suggesting considerably increased risk of hemolytic anemia upon exposure to aminoquinolines. Combined, our results reveal the unique genetic landscape of the Gabonese population and pinpoint the genetic basis for inter-individual differences in antimalarial drug response and toxicity.

The neuronal network of the endogenous clock

e-Neuroforum ◽  
2010 ◽  
Vol 16 (1) ◽  
Author(s):  
Charlotte Förster
Keyword(s):  
Molecular Basis ◽  
Clock Genes ◽  
Fruit Fly ◽  
Biological Processes ◽  
Rhythm Generation ◽  
The Metabolic Syndrome ◽  
Clock Network ◽  
Endogenous Clock ◽  
The Brain

AbstractEndogenous clocks control the rhythm of many biological processes. Malfunction of endogenous clocks in humans can lead to various diseases as sleep disorders, depres­sions, the metabolic syndrome and cancer. All animals have a main clock in the brain. This clock comprises a network of clock neurons that communicate with each other. In each clock neuron, conserved clock genes and pro­teins interact in to generate a molecular os­cillation. The molecular basis of this rhythm generation as well as the anatomy of the neuronal clock network is best investigated in the fruit fly Drosophila melanogaster. In the little fly, clock genes can be shut down in specific clock neurons. Furthermore, specific clock neurons can be electrically silenced and the rhythmic behaviour of such manipulated flies can be studied. A flurry of recent studies has begun to identify the role of specific clock neurons in the clock network, and these find­ings are helping to understand the basic neu­ronal mechanisms of endogenous clocks.

scholarly journals Experimental approaches for addressing fundamental biological questions in living, functioning cells with single molecule precision

Open Biology ◽  
2012 ◽  
Vol 2 (6) ◽  
pp. 120090 ◽  
Author(s):  
Tchern Lenn ◽  
Mark C. Leake
Keyword(s):  
Single Molecule ◽  
Molecular Basis ◽  
Life Sciences ◽  
Short Review ◽  
Living Cells ◽  
Cellular Systems ◽  
Biological Processes ◽  
Sensitivity Level ◽  
Experimental Approaches ◽  
The Impact

In recent years, single molecule experimentation has allowed researchers to observe biological processes at the sensitivity level of single molecules in actual functioning, living cells, thereby allowing us to observe the molecular basis of the key mechanistic processes in question in a very direct way, rather than inferring these from ensemble average data gained from traditional molecular and biochemical techniques. In this short review, we demonstrate the impact that the application of single molecule bioscience experimentation has had on our understanding of various cellular systems and processes, and the potential that this approach has for the future to really address very challenging and fundamental questions in the life sciences.

Methotrexate pharmacogenetics in the treatment of rheumatoid arthritis

2019 ◽  
Vol 20 (17) ◽  
pp. 1235-1245 ◽  
Author(s):  
Biljana Jekic ◽  
Nela Maksimovic ◽  
Tatjana Damnjanovic
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Basis ◽  
Therapeutic Response ◽  
Short Review ◽  
Therapy Outcomes ◽  
Therapy Failure ◽  
Drug Of Choice ◽  
Number Of Patients ◽  
Study Results

For many decades, methotrexate (MXT) has remained the drug of choice in the treatment of rheumatoid arthritis (RA). Unfortunately, a considerable number of patients do not achieve an appropriate therapeutic response. Pharmacogenetics studies do not give usable results regarding differences in MTX response among RA patients. The mechanism of MTX action in RA is not completely understood. We present and discuss data regarding the molecular basis of folate and adenosine pathways, the most obvious MTX targets, to explain possible causes of therapy failure. The molecular basis of the disease could also have an impact on therapy outcomes and in this review we explore this. Finally, we make a short review of available pharmacogenetics study results.

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