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  • 1
    Language: English
    In: Nucleic acids research, 2020-07-02, Vol.48 (W1), p.W162-W169
    Description: Abstract VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.
    Subject(s): AcademicSubjects ; SCI00010 ; Web Server Issue
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: American journal of human genetics, 2017-11-02, Vol.101 (5), p.833-843
    Description: Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G〉A (p.Arg217His) and c.649C〉T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands’ cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands’ fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.
    Subject(s): Abnormalities, Multiple - genetics ; Adenosine Triphosphate - genetics ; Adolescent ; Antiporters - genetics ; Calcium-Binding Proteins - genetics ; Child ; Child, Preschool ; Craniofacial Abnormalities - genetics ; Craniosynostoses - genetics ; Craniosynostosis ; Cutis laxa ; Cutis Laxa - genetics ; DNA, Mitochondrial - genetics ; Ductus Arteriosus, Patent - genetics ; Exome - genetics ; Female ; Fetal Growth Retardation - genetics ; Fibroblasts - pathology ; Gorlin-Chaudhry-Moss syndrome ; Humans ; Hydrogen Peroxide - pharmacology ; Hypertrichosis ; Hypertrichosis - genetics ; Infant ; Lipoatrophy ; Membrane Potential, Mitochondrial - drug effects ; Membrane Potential, Mitochondrial - genetics ; Mitochondria - drug effects ; Mitochondria - genetics ; Mitochondrial Proteins - genetics ; Mitochondrial swelling ; Mutation - genetics ; Oxidative stress ; Oxidative Stress - genetics ; Premature aging ; Progeria - genetics ; Report ; SLC25A24
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 3
    Language: English
    In: American journal of human genetics, 2019-09-05, Vol.105 (3), p.631-639
    Description: Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.
    Subject(s): autism ; brain malformation ; Calcium-Binding Proteins - genetics ; Cellular signal transduction ; Cohort Studies ; developmental delay ; DLL1 ; Female ; Genetic aspects ; Genetics & Heredity ; Haploinsufficiency ; Humans ; intellectual disability ; Life Sciences & Biomedicine ; Ligands ; Male ; Membrane Proteins - genetics ; Mental retardation ; Neurodevelopmental Disorders - genetics ; Notch signaling ; Pedigree ; Physiological aspects ; Report ; Research ; Risk factors ; Science & Technology ; vertebral segmentation defects ; Whole Exome Sequencing
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
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  • 4
    Language: English
    In: Human genetics, 2018-08-23, Vol.137 (9), p.753-768
    Description: NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
    Subject(s): Adolescent ; Adult ; Biomedical and Life Sciences ; Biomedicine ; Carrier Proteins - genetics ; Channelopathies - genetics ; Channelopathies - pathology ; Child ; Child, Preschool ; Developmental Disabilities - genetics ; Developmental Disabilities - pathology ; Excitability ; Female ; Gene Function ; Genetic aspects ; Genetic Markers ; Genetic variance ; Genetic Variation ; Genetics ; Human Genetics ; Humans ; Infant ; Infant, Newborn ; Intellectual disabilities ; Lamotrigine ; Life Sciences ; Male ; Medical colleges ; Membrane potential ; Membrane Proteins - genetics ; Metabolic Diseases ; Molecular Medicine ; Neurodevelopmental disorders ; Neurophysiology ; Original Investigation ; Phenotype ; Phenotypes ; Sodium ; Sodium Channels - genetics ; Young Adult
    ISSN: 0340-6717
    E-ISSN: 1432-1203
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Genetics in medicine, 2019-08-01, Vol.21 (8), p.1797-1807
    Description: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
    Subject(s): Adolescent ; Autism ; Autism Spectrum Disorder - genetics ; Autism Spectrum Disorder - physiopathology ; Behavior ; Child ; Child, Preschool ; Chromosome Deletion ; Chromosomes ; corpus callosum thinning ; DNA-Binding Proteins - genetics ; Family medical history ; Genetic counseling ; Genetics ; Genetics & Heredity ; Genetics(clinical) ; Genome, Human - genetics ; Genomes ; Genotype & phenotype ; Haploinsufficiency - genetics ; Hospitals ; Humans ; Infant ; Infant, Newborn ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Laboratories ; Language Development Disorders - genetics ; Language Development Disorders - physiopathology ; Life Sciences & Biomedicine ; Medical records ; Medicine ; neurodevelopment ; Neurodevelopmental Disorders - genetics ; Neurodevelopmental Disorders - physiopathology ; Nuclear Proteins - genetics ; Patients ; Pediatrics ; Phenotype ; Problem Behavior ; Proteins ; Proteins - genetics ; Science & Technology ; speech delay ; USP7 ; white matter paucity ; Whole Exome Sequencing
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Genetics in medicine, 2019-08-01, Vol.21 (8), p.1797-1807
    Description: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
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  • 7
    Language: English
    Description: Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
    Subject(s): corpus callosum thinning ; Genetics(clinical) ; neurodevelopment ; speech delay ; USP7 ; white matter paucity
    ISSN: 1098-3600
    E-ISSN: 1530-0366
    Source: Utrecht University Repository
    Source: Alma/SFX Local Collection
    Library Location Call Number Volume/Issue/Year Availability
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  • 8
    Language: English
    Description: VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.
    Subject(s): ddc:610 ; Genetic Variation ; Molecular Sequence Annotation ; Rare Diseases ; User-Computer Interface
    Source: Dokumentenserver der FU Berlin
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