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  • 1
    Language: English
    In: Clinical epigenetics, 2019-06-11, Vol.11 (1), p.89-89
    Description: BackgroundCardiac disease modelling using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) requires thorough insight into cardiac cell type differentiation processes. However, current methods to discriminate different cardiac cell types are mostly time-consuming, are costly and often provide imprecise phenotypic evaluation. DNA methylation plays a critical role during early heart development and cardiac cellular specification. We therefore investigated the DNA methylation pattern in different cardiac tissues to identify CpG loci for further cardiac cell type characterization.ResultsAn array-based genome-wide DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChips led to the identification of 168 differentially methylated CpG loci in atrial and ventricular human heart tissue samples (n=49) from different patients with congenital heart defects (CHD). Systematic evaluation of atrial-ventricular DNA methylation pattern in cardiac tissues in an independent sample cohort of non-failing donor hearts and cardiac patients using bisulfite pyrosequencing helped us to define a subset of 16 differentially methylated CpG loci enabling precise characterization of human atrial and ventricular cardiac tissue samples. This defined set of reproducible cardiac tissue-specific DNA methylation sites allowed us to consistently detect the cellular identity of hiPSC-CM subtypes.ConclusionTesting DNA methylation of only a small set of defined CpG sites thus makes it possible to distinguish atrial and ventricular cardiac tissues and cardiac atrial and ventricular subtypes of hiPSC-CMs. This method represents a rapid and reliable system for phenotypic characterization of in vitro-generated cardiomyocytes and opens new opportunities for cardiovascular research and patient-specific therapy.
    Subject(s): 450K array ; Analysis ; Birth defects ; Bisulfite ; Bisulfite pyrosequencing ; Cardiac patients ; Cardiac tissue-specific DNA methylation ; Cardiomyocytes ; Cell differentiation ; Cells, Cultured ; Congenital diseases ; Congenital heart disease ; Coronary artery disease ; CpG Islands ; Deoxyribonucleic acid ; Developmental biology ; Developmental disabilities ; Disease control ; DNA ; DNA fingerprinting ; DNA Methylation ; Engineered heart tissue (EHT) ; Epigenetics ; Female ; Gene expression ; Genetic disorders ; Genetics & Heredity ; Genomes ; Genomics ; Heart ; Heart Atria - chemistry ; Heart Atria - cytology ; Heart Defects, Congenital - genetics ; Heart Defects, Congenital - pathology ; Heart diseases ; Heart Ventricles - chemistry ; Heart Ventricles - cytology ; Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) ; Humans ; Induced Pluripotent Stem Cells - chemistry ; Induced Pluripotent Stem Cells - cytology ; Life Sciences & Biomedicine ; Male ; Medical research ; Medicine, Experimental ; Methylation ; Models, Biological ; Myocytes, Cardiac - chemistry ; Myocytes, Cardiac - cytology ; Oncology ; Organ Specificity ; Pluripotency ; Principal components analysis ; Research ; Science & Technology ; Sequence Analysis, DNA ; Stem cells ; Sulfites ; Tissue Engineering ; Transplantation ; Ventricle
    ISSN: 1868-7075
    ISSN: 1868-7083
    E-ISSN: 1868-7083
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: SpringerLink Contemporary (1997 - Present)
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  • 2
    Article
    Article
    2017
    ISSN: 0936-5931 
    Language: German
    In: Medizinische Genetik, 2017-06-26, Vol.29 (2), p.248-256
    Description: Zusammenfassung Strukturelle Herzfehler sind eine der häufigsten menschlichen Fehlbildungen. Es lassen sich mehrere morphologische Gruppen unterscheiden, wobei auch Überlappungen mit verschiedenen Formen der Kardiomyopathien, unter anderem mit der Non-Compaction Kardiomyopathie, beobachtet werden. Zum jetzigen Zeitpunkt liegt nur ein sehr eingeschränktes Verständnis der zugrunde liegenden genetischen Ursachen vor. Dies liegt zum einen an einer „komplexen Genetik“, bei welcher häufig reduzierte Penetranz und variable Expressivität vorliegen, zum anderen aber auch an heterogenen Literaturangaben, bei denen nur unzureichende genetische Evidenzen bestehen. Der Fokus dieses Reviews ist es, anhand von stringenten Evidenzkriterien die bekannten Gene für strukturelle Herzfehler darzustellen. Speziell durch die Nutzung von Next Generation Sequencing (NGS) können zunehmend mehr relevante genetische Zusammenhänge geklärt werden. Dies gilt nicht nur für die Validierung von Genotyp-Phänotyp-Assoziationen, sondern auch für die Identifizierung neuer Gene für angeborene Herzfehler (AHF), was besonders wegen des seltenen Vorkommens rekurrenter AHF-assoziierter Mutationen im gleichen Gen in Zukunft notwendig sein wird. Um dieses Ziel zu erreichen, ist es notwendig, große deutschlandweite oder internationale Studien zu etablieren und bereits publizierte Datensätze öffentlich zugänglich zu machen. Dies sollte auch für diagnostische Datensätze gelten. Mit einem derartigen Ansatz könnte nicht nur eine Gen-Panel-Diagnostik, sondern auch die Eingruppierung der Herzfehler in therapeutische Subgruppen erreicht werden.
    Subject(s): Aus Klinik und Praxis ; Compaction ; Gene Therapy ; general ; Gynecology ; Human Genetics ; Medicine ; Medicine & Public Health ; Oncology ; Reproductive Medicine
    ISSN: 0936-5931
    E-ISSN: 1863-5490
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: The Journal of immunology (1950), 2011-03-15, Vol.186 (6), p.3364-3372
    Description: The chemokine receptor CCR7 represents an important determinant for circulating lymphocytes to enter lymph nodes (LN) via high endothelial venules. High endothelial venules also represent the major site of entry for plasmacytoid dendritic cells (pDC). In the steady-state, murine pDC have been suggested to home to LN engaging the chemokine receptors CXCR3, CXCR4, and CCR5, whereas responsiveness to CCR7 ligands is thought to be acquired only upon activation. In this study, we show that already resting pDC express minute amounts of CCR7 that suffice to trigger migration to CCL19/CCL21 in vitro. Upon activation with TLR ligands, CCR7 levels on pDC are strongly increased. Notably, CCR7-deficient mice display substantially reduced pDC counts in LN but not in bone marrow and spleen. Adoptive cell transfer experiments revealed that under both steady-state as well as inflammatory conditions, the homing of CCR7-deficient pDC is severely impaired, indicating that the reduced cell counts of naive pDC observed in CCR7(-/-) mice reflect an intrinsic homing defect of pDC. Together, these observations provide strong evidence that similar to naive lymphocytes, nonstimulated pDC exploit CCR7 to gain entry into LN. This adds to the repertoire of chemokine receptors permitting them to enter diverse tissues.
    Subject(s): Abridged Index Medicus ; Adoptive Transfer ; Animals ; Cell Movement - genetics ; Cell Movement - immunology ; Dendritic Cells - immunology ; Dendritic Cells - pathology ; Dendritic Cells - transplantation ; Inflammation Mediators - metabolism ; Inflammation Mediators - physiology ; Lymph Nodes - cytology ; Lymph Nodes - immunology ; Lymph Nodes - pathology ; Melanoma, Experimental - immunology ; Melanoma, Experimental - pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, CCR7 - biosynthesis ; Receptors, CCR7 - deficiency ; Receptors, CCR7 - physiology ; Receptors, Lymphocyte Homing - deficiency ; Receptors, Lymphocyte Homing - genetics ; Receptors, Lymphocyte Homing - physiology ; Resting Phase, Cell Cycle - genetics ; Resting Phase, Cell Cycle - immunology
    ISSN: 0022-1767
    E-ISSN: 1550-6606
    Source: HighWire Press (Free Journals)
    Source: Alma/SFX Local Collection
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  • 4
    Article
    Article
    2017
    ISSN: 0936-5931 
    Language: English
    In: Medizinische Genetik, 2017-06-01, Vol.29 (2), p.248-256
    Description: Strukturelle Herzfehler sind eine der häufigsten menschlichen Fehlbildungen. Es lassen sich mehrere morphologische Gruppen unterscheiden, wobei auch Überlappungen mit verschiedenen Formen der Kardiomyopathien, unter anderem mit der Non-Compaction Kardiomyopathie, beobachtet werden. Zum jetzigen Zeitpunkt liegt nur ein sehr eingeschränktes Verständnis der zugrunde liegenden genetischen Ursachen vor. Dies liegt zum einen an einer „komplexen Genetik“, bei welcher häufig reduzierte Penetranz und variable Expressivität vorliegen, zum anderen aber auch an heterogenen Literaturangaben, bei denen nur unzureichende genetische Evidenzen bestehen. Der Fokus dieses Reviews ist es, anhand von stringenten Evidenzkriterien die bekannten Gene für strukturelle Herzfehler darzustellen. Speziell durch die Nutzung von Next Generation Sequencing (NGS) können zunehmend mehr relevante genetische Zusammenhänge geklärt werden. Dies gilt nicht nur für die Validierung von Genotyp-Phänotyp-Assoziationen, sondern auch für die Identifizierung neuer Gene für angeborene Herzfehler (AHF), was besonders wegen des seltenen Vorkommens rekurrenter AHF-assoziierter Mutationen im gleichen Gen in Zukunft notwendig sein wird. Um dieses Ziel zu erreichen, ist es notwendig, große deutschlandweite oder internationale Studien zu etablieren und bereits publizierte Datensätze öffentlich zugänglich zu machen. Dies sollte auch für diagnostische Datensätze gelten. Mit einem derartigen Ansatz könnte nicht nur eine Gen-Panel-Diagnostik, sondern auch die Eingruppierung der Herzfehler in therapeutische Subgruppen erreicht werden.
    Subject(s): Genetics of congenital heart defects ; Genetik angeborener Herzfehler ; Nicht-syndromal ; Non-compaction cardiomyopathy ; Non-Compaction Kardiomyopathie ; Non-syndromic ; Syndromal ; Syndromic
    ISSN: 0936-5931
    E-ISSN: 1863-5490
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Medizinische Genetik, 2017-06-01, Vol.29 (2), p.248
    Description: Byline: Anne-Karin Kahlert (1,2,3), Kirstin Hoff (1,3,4), Marc-Phillip Hitz (1,3,4,5) Keywords: Genetik angeborener Herzfehler; Syndromal; Nicht-syndromal; Non-Compaction Kardiomyopathie; Genetics of congenital heart defects; Syndromic; Non-syndromic; Non-compaction cardiomyopathy (German): Strukturelle Herzfehler sind eine der haufigsten menschlichen Fehlbildungen. Es lassen sich mehrere morphologische Gruppen unterscheiden, wobei auch Uberlappungen mit verschiedenen Formen der Kardiomyopathien, unter anderem mit der Non-Compaction Kardiomyopathie, beobachtet werden. Zum jetzigen Zeitpunkt liegt nur ein sehr eingeschranktes Verstandnis der zugrunde liegenden genetischen Ursachen vor. Dies liegt zum einen an einer "komplexen Genetik", bei welcher haufig reduzierte Penetranz und variable Expressivitat vorliegen, zum anderen aber auch an heterogenen Literaturangaben, bei denen nur unzureichende genetische Evidenzen bestehen. Der Fokus dieses Reviews ist es, anhand von stringenten Evidenzkriterien die bekannten Gene fur strukturelle Herzfehler darzustellen. Speziell durch die Nutzung von Next Generation Sequencing (NGS) konnen zunehmend mehr relevante genetische Zusammenhange geklart werden. Dies gilt nicht nur fur die Validierung von Genotyp-Phanotyp-Assoziationen, sondern auch fur die Identifizierung neuer Gene fur angeborene Herzfehler (AHF), was besonders wegen des seltenen Vorkommens rekurrenter AHF-assoziierter Mutationen im gleichen Gen in Zukunft notwendig sein wird. Um dieses Ziel zu erreichen, ist es notwendig, gro[sz]e deutschlandweite oder internationale Studien zu etablieren und bereits publizierte Datensatze offentlich zuganglich zu machen. Dies sollte auch fur diagnostische Datensatze gelten. Mit einem derartigen Ansatz konnte nicht nur eine Gen-Panel-Diagnostik, sondern auch die Eingruppierung der Herzfehler in therapeutische Subgruppen erreicht werden. Congenital heart disease (CHD) is the most common congenital malformation in humans. Morphologically, it is possible to distinguish different forms, some of which, such as non-compaction cardiomyopathy, show a significant overlap with cardiomyopathies. Currently, our understanding of the underlying genetics is limited, because of its complexity, in which reduced penetrance and variable expressivity are often observed. In addition, the available literature is often diverse, and consists of inadequate genetic evidence. Therefore, the focus of this review is to present the genes known to be involved in CHD, based on stringent criteria. With the use of next generation sequencing (NGS) technologies, an increasing number of relevant genetic connections can be clarified. It not only helps to establish strong genotype--phenotype associations, but also to identify novel CHD genes, which will be urgently needed in the future given the rare occurrence of recurrent CHD-associated mutations in the same gene. To achieve this goal, it will be necessary to establish nationwide and international studies and make published datasets available to the community. The same applies to diagnostic datasets. Such an approach would be helpful in obtaining gene panel diagnostics and in classifying CHD into therapeutic subgroups. Author Affiliation: (1) Klinik fur angeborene Herzfehler und Kinderkardiologie, Universitatsklinikum Schleswig-Holstein Campus Kiel, Kiel, Deutschland (2) Institut fur Klinische Genetik, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Deutschland (3) DZHK (Deutsches Zentrum fur Herz- und Kreislaufforschung), Standort Hamburg/Kiel/Lubeck, Kiel, Deutschland (4) Institut fur Humangenetik, Universitatsklinikum Schleswig-Holstein Campus Kiel, Kiel, Deutschland (5) Wellcome Trust Sanger Institute, Cambridge, Gro[sz]britannien Article History: Registration Date: 23/05/2017 Online Date: 26/06/2017
    Subject(s): Congenital heart disease ; Genes ; Genetic aspects ; Genetic disorders ; Heart diseases
    ISSN: 0936-5931
    E-ISSN: 1863-5490
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: American journal of human genetics, 2014-12-04, Vol.95 (6), p.763-770
    Description: Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A〉G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G〉T (p.Ala100Ser), c.294T〉G (p.Phe98Leu), c.269A〉G (p.Glu90Gly), and c.700T〉C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G〉T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
    Subject(s): Adolescent ; Adult ; Amino Acid Sequence ; Amino acids ; Causes of ; Child, Preschool ; Exome - genetics ; Female ; Gene mutations ; Genetic disorders ; Genetic research ; Hand Deformities, Congenital - enzymology ; Hand Deformities, Congenital - genetics ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Infant ; Male ; Metabolism ; Middle Aged ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Oxidoreductases - genetics ; Oxidoreductases - metabolism ; Pedigree ; Pierre Robin Syndrome - enzymology ; Pierre Robin Syndrome - genetics ; Report ; Research ; Sequence Alignment ; Sequence Analysis, DNA ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 7
    Language: English
    Description: Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
    Subject(s): Journal Article
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Manchester University Research Explorer
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    Description: Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters. publisher: Elsevier articletitle: Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2014.03.007 content_type: article copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. status: published
    ISSN: 1537-6605
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Lirias (KU Leuven Association)
    Source: PubMed Central
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  • 9
    Language: English
    In: PLoS genetics, 2021-09-21, Vol.17 (7)
    Description: The thirteenth author's name is spelled incorrectly. The correct name is: D. Woodrow Benson.
    ISSN: 1553-7390
    E-ISSN: 1553-7404
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    Description: Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. status: published
    ISSN: 1553-7404
    E-ISSN: 1553-7404
    Source: Lirias (KU Leuven Association)
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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