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Article ; Online: Global developmental delay and a de novo deletion of the 16p13.13 region.

Krakowski, Aneta / Hoang, Ny / Trost, Brett / Summers, Jane / Ambrozewicz, Patricia / Vorstman, Jacob

BMJ case reports

2024 Volume 17, Issue 2

Abstract: Many rare genetic variants are associated with the risk of atypical neurodevelopmental trajectories. In this study, we report a patient with developmental delay, autistic traits and multiple congenital anomalies, including congenital heart anomalies and ... ...

Abstract	Many rare genetic variants are associated with the risk of atypical neurodevelopmental trajectories. In this study, we report a patient with developmental delay, autistic traits and multiple congenital anomalies, including congenital heart anomalies and orofacial cleft, with a 0.832 Mb de novo deletion of the 16p13.13 region classified as a variant of uncertain significance. Comparison of similar sized deletions and duplications overlapping the same genes in the DECIPHER database, revealed seven reports of copy number variants (CNVs), four duplications and three deletions. A neurodevelopmental phenotype including learning disability and intellectual disability was noted in some of the DECIPHER entries where phenotype was provided. Although the association between a deletion in this region and an atypical neurodevelopmental trajectory remains to be elucidated, the overlapping CNVs with neurodevelopmental phenotypes suggests possible candidate genes within the 16p13.13 region.
MeSH term(s)	Humans ; Cleft Lip ; Cleft Palate ; Intellectual Disability/genetics ; Abnormalities, Multiple/genetics ; DNA Copy Number Variations/genetics
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Case Reports ; Journal Article
ISSN	1757-790X
ISSN (online)	1757-790X
DOI	10.1136/bcr-2022-251521
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Article ; Online: Complex Autism Spectrum Disorder in a Patient with a Novel De Novo Heterozygous

Yip, Silas / Calli, Kristina / Qiao, Ying / Trost, Brett / Scherer, Stephen W / Lewis, M E Suzanne

Genes

2023 Volume 14, Issue 12

Abstract: Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin ... ...

Abstract	Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a proband with complex ASD. Whole genome sequencing revealed a novel de novo missense mutation of a highly conserved amino acid residue (NP_001289981.1:p.His516Gln; chr2:1917275; hg38) in the
MeSH term(s)	Humans ; Autism Spectrum Disorder/genetics ; Phenotype ; Mutation, Missense ; Genetic Association Studies ; Gene Expression Regulation ; Nerve Tissue Proteins/genetics ; Transcription Factors/genetics
Chemical Substances	MYT1L protein, human ; Nerve Tissue Proteins ; Transcription Factors
Language	English
Publishing date	2023-11-24
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14122122
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Article ; Online: Discovery of genomic variation across a generation.

Trost, Brett / Loureiro, Livia O / Scherer, Stephen W

Human molecular genetics

2020 Volume 30, Issue R2, Page(s) R174–R186

Abstract: Over the past 30 years (the timespan of a generation), advances in genomics technologies have revealed tremendous and unexpected variation in the human genome and have provided increasingly accurate answers to long-standing questions of how much genetic ... ...

Abstract	Over the past 30 years (the timespan of a generation), advances in genomics technologies have revealed tremendous and unexpected variation in the human genome and have provided increasingly accurate answers to long-standing questions of how much genetic variation exists in human populations and to what degree the DNA complement changes between parents and offspring. Tracking the characteristics of these inherited and spontaneous (or de novo) variations has been the basis of the study of human genetic disease. From genome-wide microarray and next-generation sequencing scans, we now know that each human genome contains over 3 million single nucleotide variants when compared with the ~ 3 billion base pairs in the human reference genome, along with roughly an order of magnitude more DNA-approximately 30 megabase pairs (Mb)-being 'structurally variable', mostly in the form of indels and copy number changes. Additional large-scale variations include balanced inversions (average of 18 Mb) and complex, difficult-to-resolve alterations. Collectively, ~1% of an individual's genome will differ from the human reference sequence. When comparing across a generation, fewer than 100 new genetic variants are typically detected in the euchromatic portion of a child's genome. Driven by increasingly higher-resolution and higher-throughput sequencing technologies, newer and more accurate databases of genetic variation (for instance, more comprehensive structural variation data and phasing of combinations of variants along chromosomes) of worldwide populations will emerge to underpin the next era of discovery in human molecular genetics.
MeSH term(s)	Female ; Genetic Variation ; Genome, Human ; Genome-Wide Association Study ; Genomics/methods ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Mutation ; Whole Genome Sequencing
Language	English
Publishing date	2020-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab209
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Article ; Online: Conservation of kinase-phosphorylation site pairings: Evidence for an evolutionarily dynamic phosphoproteome.

McDonald, Megan / Trost, Brett / Napper, Scott

PloS one

2018 Volume 13, Issue 8, Page(s) e0202036

Abstract: Kinase-mediated protein phosphorylation is a central mechanism for regulation of cellular responses and phenotypes. While considerable information is available regarding the evolutionary relationships within the kinase family, as well as the evolutionary ...

Abstract	Kinase-mediated protein phosphorylation is a central mechanism for regulation of cellular responses and phenotypes. While considerable information is available regarding the evolutionary relationships within the kinase family, as well as the evolutionary conservation of phosphorylation sites, each aspect of this partnership is typically considered in isolation, despite their clear functional relationship. Here, to offer a more holistic perspective on the evolution of protein phosphorylation, the conservation of protein phosphorylation sites is considered in the context of the conservation of the corresponding modifying kinases. Specifically, conservation of defined kinase-phosphorylation site pairings (KPSPs), as well as of each of the component parts (the kinase and the phosphorylation site), were examined across a range of species. As expected, greater evolutionary distance between species was generally associated with lower probability of KPSP conservation, and only a small fraction of KPSPs were maintained across all species, with the vast majority of KPSP losses due to the absence of the phosphorylation site. This supports a model in which a relatively stable kinome promotes the emergence of functional substrates from an evolutionarily malleable phosphoproteome.
MeSH term(s)	Animals ; Biological Evolution ; Humans ; Models, Biological ; Phosphoproteins/metabolism ; Phosphorylation ; Phosphotransferases/metabolism ; Proteome ; Proteomics/methods
Chemical Substances	Phosphoproteins ; Proteome ; Phosphotransferases (EC 2.7.-)
Language	English
Publishing date	2018-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0202036
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Article ; Online: Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous

Evans, Daniel R / Qiao, Ying / Trost, Brett / Calli, Kristina / Martell, Sally / Jones, Steven J M / Scherer, Stephen W / Lewis, M E Suzanne

Genes

2022 Volume 13, Issue 3

Abstract: Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated ... ...

Abstract	Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called ‘Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities’ (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband−parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.
MeSH term(s)	Autism Spectrum Disorder/genetics ; DNA-Directed RNA Polymerases/genetics ; Epilepsy/genetics ; Humans ; Intellectual Disability/genetics ; Muscle Hypotonia/genetics ; Self-Injurious Behavior ; Strabismus/genetics
Chemical Substances	DNA-Directed RNA Polymerases (EC 2.7.7.6) ; POLR2A RNA polymerase, human (EC 2.7.7.6)
Language	English
Publishing date	2022-03-07
Publishing country	Switzerland
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13030470
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Article ; Online: Temporal analysis of enhancers during mouse cerebellar development reveals dynamic and novel regulatory functions.

Ramirez, Miguel / Badayeva, Yuliya / Yeung, Joanna / Wu, Joshua / Abdalla-Wyse, Ayasha / Yang, Erin / Trost, Brett / Scherer, Stephen W / Goldowitz, Daniel

eLife

2022 Volume 11

Abstract: We have identified active enhancers in the mouse cerebellum at embryonic and postnatal stages which provides a view of novel enhancers active during cerebellar development. The majority of cerebellar enhancers have dynamic activity between embryonic and ... ...

Abstract	We have identified active enhancers in the mouse cerebellum at embryonic and postnatal stages which provides a view of novel enhancers active during cerebellar development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Furthermore, by comparing our data with relevant brain development ENCODE histone profiles and cerebellar single-cell datasets we have been able to generalize and expand on the presented analyses, respectively. We have made the results of our analyses available online in the Developing Mouse Cerebellum Enhancer Atlas, where our dataset can be efficiently queried, curated and exported by the scientific community to facilitate future research efforts. Our study provides a valuable resource for studying the dynamics of gene expression regulation by enhancers in the developing cerebellum and delivers a rich dataset of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.
MeSH term(s)	Animals ; Autism Spectrum Disorder/genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Mice ; Neurogenesis/genetics ; Transcription Factors/metabolism
Chemical Substances	Transcription Factors
Language	English
Publishing date	2022-08-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.74207
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Article: Complex Autism Spectrum Disorder with Epilepsy, Strabismus and Self-Injurious Behaviors in a Patient with a De Novo Heterozygous POLR2A Variant

Evans, Daniel R. / Qiao, Ying / Trost, Brett / Calli, Kristina / Martell, Sally / Jones, Steven J. M. / Scherer, Stephen W. / Lewis, M. E. Suzanne

Genes. 2022 Mar. 07, v. 13, no. 3

2022

Abstract	Autism spectrum disorder (ASD) describes a complex and heterogenous group of neurodevelopmental disorders. Whole genome sequencing continues to shed light on the multifactorial etiology of ASD. Dysregulated transcriptional pathways have been implicated in neurodevelopmental disorders. Emerging evidence suggests that de novo POLR2A variants cause a newly described phenotype called ‘Neurodevelopmental Disorder with Hypotonia and Variable Intellectual and Behavioral Abnormalities’ (NEDHIB). The variable phenotype manifests with a spectrum of features; primarily early onset hypotonia and delay in developmental milestones. In this study, we investigate a patient with complex ASD involving epilepsy and strabismus. Whole genome sequencing of the proband–parent trio uncovered a novel de novo POLR2A variant (c.1367T>C, p. Val456Ala) in the proband. The variant appears deleterious according to in silico tools. We describe the phenotype in our patient, who is now 31 years old, draw connections between the previously reported phenotypes and further delineate this emerging neurodevelopmental phenotype. This study sheds new insights into this neurodevelopmental disorder, and more broadly, the genetic etiology of ASD.
Keywords	autism ; computer simulation ; epilepsy ; etiology ; heterozygosity ; patients ; phenotype ; transcription (genetics)
Language	English
Dates of publication	2022-0307
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13030470
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples.

Woodbury-Smith, Marc / D'Abate, Lia / Stavropoulos, Dimitri J / Howe, Jennifer / Drmic, Irene / Hoang, Ny / Zarrei, Mehdi / Trost, Brett / Iaboni, Alana / Anagnostou, Evdokia / Scherer, Stephen W

Journal of medical genetics

2023 Volume 60, Issue 12, Page(s) 1153–1160

Abstract: Background: We present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2-BP3). Genomic analysis of all family members was ... ...

Abstract	Background: We present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2-BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index. Methods: All male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities. Results: On medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with mild attention deficits. The third-born male offspring was only noted as having motor deficits and received a diagnosis of developmental coordination disorder. Other than the 16p11.2 distal deletion, no additional contributing variants of clinical significance were observed. The mother was clinically evaluated and noted as having a broader autism phenotype. Conclusion: In this family, the phenotypes observed are most likely caused by the 16p11.2 distal deletion. The lack of other overt pathogenic mutations identified by genomic sequencing reinforces the variable expressivity that should be heeded in a clinical setting. Importantly, distal 16p11.2 deletions can present with a highly variable phenotype even within a single family. Our additional data curation provides further evidence on the variable clinical presentation among those with pathogenetic 16p11.2 (BP2-BP3) mutations.
MeSH term(s)	Child ; Humans ; Male ; Chromosome Deletion ; Autism Spectrum Disorder/diagnosis ; Autism Spectrum Disorder/genetics ; Autistic Disorder/genetics ; Family ; Phenotype ; Biological Variation, Population ; Chromosomes, Human, Pair 16/genetics ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics
Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Journal Article
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmg-2022-108818
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Zs.A 177: Show issues

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Article ; Online: Technological advances for interrogating the human kinome.

Baharani, Akanksha / Trost, Brett / Kusalik, Anthony / Napper, Scott

Biochemical Society transactions

2017 Volume 45, Issue 1, Page(s) 65–77

Abstract: There is increasing appreciation among researchers and clinicians of the value of investigating biology and pathobiology at the level of cellular kinase (kinome) activity. Kinome analysis provides valuable opportunity to gain insights into complex ... ...

Abstract	There is increasing appreciation among researchers and clinicians of the value of investigating biology and pathobiology at the level of cellular kinase (kinome) activity. Kinome analysis provides valuable opportunity to gain insights into complex biology (including disease pathology), identify biomarkers of critical phenotypes (including disease prognosis and evaluation of therapeutic efficacy), and identify targets for therapeutic intervention through kinase inhibitors. The growing interest in kinome analysis has fueled efforts to develop and optimize technologies that enable characterization of phosphorylation-mediated signaling events in a cost-effective, high-throughput manner. In this review, we highlight recent advances to the central technologies currently available for kinome profiling and offer our perspectives on the key challenges remaining to be addressed.
MeSH term(s)	Animals ; Humans ; Phosphorylation ; Protein Array Analysis/methods ; Protein Kinases/metabolism ; Proteome/metabolism ; Proteomics/methods ; Reproducibility of Results ; Signal Transduction
Chemical Substances	Proteome ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2017-02-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20160163
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Zs.A 944: Show issues

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Article ; Online: Computational phosphorylation site prediction in plants using random forests and organism-specific instance weights.

Trost, Brett / Kusalik, Anthony

Bioinformatics (Oxford, England)

2013 Volume 29, Issue 6, Page(s) 686–694

Abstract: Motivation: Phosphorylation is the most important post-translational modification in eukaryotes. Although many computational phosphorylation site prediction tools exist for mammals, and a few were created specifically for Arabidopsis thaliana, none are ... ...

Abstract	Motivation: Phosphorylation is the most important post-translational modification in eukaryotes. Although many computational phosphorylation site prediction tools exist for mammals, and a few were created specifically for Arabidopsis thaliana, none are currently available for other plants. Results: In this article, we propose a novel random forest-based method called PHOSFER (PHOsphorylation Site FindER) for applying phosphorylation data from other organisms to enhance the accuracy of predictions in a target organism. As a test case, PHOSFER is applied to phosphorylation sites in soybean, and we show that it more accurately predicts soybean sites than both the existing Arabidopsis-specific predictors, and a simpler machine-learning scheme that uses only known phosphorylation sites and non-phosphorylation sites from soybean. In addition to soybean, PHOSFER will be extended to other organisms in the near future.
MeSH term(s)	Animals ; Artificial Intelligence ; Cattle ; Computational Biology/methods ; Humans ; Mice ; Phosphorylation ; Plant Proteins/chemistry ; Plant Proteins/metabolism ; Protein Processing, Post-Translational ; Sequence Alignment ; Sequence Analysis, Protein ; Software ; Glycine max/metabolism
Chemical Substances	Plant Proteins
Language	English
Publishing date	2013-01-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btt031
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