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  • 1
    Language: English
    In: PloS one, 2015, Vol.10 (5), p.e0126321-e0126321
    Description: Next generation sequencing (NGS) has been a great success and is now a standard method of research in the life sciences. With this technology, dozens of whole genomes or hundreds of exomes can be sequenced in rather short time, producing huge amounts of data. Complex bioinformatics analyses are required to turn these data into scientific findings. In order to run these analyses fast, automated workflows implemented on high performance computers are state of the art. While providing sufficient compute power and storage to meet the NGS data challenge, high performance computing (HPC) systems require special care when utilized for high throughput processing. This is especially true if the HPC system is shared by different users. Here, stability, robustness and maintainability are as important for automated workflows as speed and throughput. To achieve all of these aims, dedicated solutions have to be developed. In this paper, we present the tricks and twists that we utilized in the implementation of our exome data processing workflow. It may serve as a guideline for other high throughput data analysis projects using a similar infrastructure. The code implementing our solutions is provided in the supporting information files.
    Subject(s): Acids ; Automatic Data Processing - methods ; Automation ; Bioinformatics ; Computation ; Computational Biology - methods ; Computers ; Computing Methodologies ; Consortia ; Data analysis ; Data processing ; Databases ; DNA sequencing ; Gene expression ; Genomes ; Genomics ; High-Throughput Nucleotide Sequencing - methods ; Humans ; Linux ; Maintainability ; Medical research ; Mutation ; Nucleotide sequencing ; Research methodology ; Researchers ; Sequence Analysis, DNA - methods ; Systems stability ; Technology application ; Usage ; Workflow
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Annals of neurology, 2014-05, Vol.75 (5), p.788-792
    Description: Recent studies reported DEPDC5 loss‐of‐function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n = 11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes. Ann Neurol 2014;75:788–792
    Subject(s): Child ; Child, Preschool ; Epilepsies, Partial - diagnosis ; Epilepsies, Partial - genetics ; Epilepsy ; Epilepsy, Rolandic - diagnosis ; Epilepsy, Rolandic - genetics ; Female ; Genetic Variation - genetics ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mutation ; Mutation - genetics ; Pedigree ; Phenotype ; TOR Serine-Threonine Kinases - genetics
    ISSN: 0364-5134
    E-ISSN: 1531-8249
    Source: Hellenic Academic Libraries Link
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  • 3
    Language: English
    In: Frontiers in genetics, 2017, Vol.8, p.130-130
    Description: In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in , c.1273G〉A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient's microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A〉T (p.Lys889 ), in , encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.
    Subject(s): consanguinity ; Genetics ; IFIH1 ; immunodeficiency ; infection ; loss-of-function ; whole-exome sequencing
    ISSN: 1664-8021
    E-ISSN: 1664-8021
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: Annals of neurology, 2017-10, Vol.82 (4), p.562-577
    Description: Objective Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho‐interacting kinase)—a component of the central spindle matrix—were added. We aimed at identifying novel MCPH‐associated genes and exploring their functional role in pathogenesis. Methods Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease‐causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. Results We identified homozygous mutations in KIF14 (NM_014875.2;c.263T〉A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G〉A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C〉G;p.His849Asp and c.3662G〉T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin‐like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient‐derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells—signs of failed cytokinesis that we also observed in experimentally KIF14‐depleted cells. Interpretation Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562–577
    Subject(s): Apoptosis ; Caspase 7 - metabolism ; Cell Movement - genetics ; Cells, Cultured ; Cerebral cortex ; Child ; Child, Preschool ; Cytokinesis ; Cytokinesis - genetics ; Etiology ; Family Health ; Female ; Fibroblasts ; Fibroblasts - physiology ; Gene Expression Regulation - genetics ; Genes ; Genome-Wide Association Study ; Humans ; Immunofluorescence ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinesin ; Kinesin - genetics ; Linkage analysis ; Localization ; Male ; Microcephaly ; Microcephaly - diagnostic imaging ; Microcephaly - genetics ; Microcephaly - pathology ; Microencephaly ; Microscopy ; Missense mutation ; Mutation ; Mutation - genetics ; Oncogene Proteins - genetics ; Pathogenesis ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Ribonucleic acid ; RNA ; Splicing ; Tubulin - metabolism
    ISSN: 0364-5134
    E-ISSN: 1531-8249
    Source: Hellenic Academic Libraries Link
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  • 5
    Language: English
    In: Clinical genetics, 2020-07, Vol.98 (1), p.32-42
    Description: Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well‐selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.
    Subject(s): clinical diagnostics ; Deafness ; Etiology ; gene panel sequencing ; genetic heterogeneity ; Hearing impairment ; Hearing loss ; Hearing protection ; Linkage analysis ; massively parallel sequencing ; nonsyndromic ; Population studies ; sensorineural
    ISSN: 0009-9163
    E-ISSN: 1399-0004
    Source: Hellenic Academic Libraries Link
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  • 6
    Language: English
    In: Annals of neurology, 2015-06-01, Vol.77 (6), p.972
    Description:   Objective To test whether mutations in [gamma]-aminobutyric acid type A receptor (GABAA-R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). Methods We performed exome sequencing to compare the frequency of variants in 18 GABAA-R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function. Results Of 18 screened GABAA-R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio=18.07, 95% confidence interval=2.01-855.07, p=0.0024, pcorr=0.043). We identified a GABRG2 splice variant (c.549-3T〉G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant [gamma]2 subunit. Interpretation The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants. Ann Neurol 2015;77:972-986
    Subject(s): Confidence intervals ; Genes ; Mutation
    ISSN: 0364-5134
    E-ISSN: 1531-8249
    Source: Hellenic Academic Libraries Link
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  • 7
    Language: English
    In: Human mutation, 2020-01, Vol.41 (1), p.169-181
    Description: Rare coding variants in the triggering receptor expressed on myeloid cells‐2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss‐of‐function variants have been reported in families with monogenic frontotemporal‐like dementia with/without bone abnormalities. In a whole‐exome sequencing study of a family with probable AD‐type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine‐to‐tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G〉T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin‐like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)‐induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD‐like form of dementia.
    Subject(s): Aged ; Alleles ; Alzheimer disease ; Alzheimer's disease ; Amino acid substitution ; Animals ; Apolipoprotein E ; Cell Line ; conformation ; Dementia ; Dementia - diagnosis ; Dementia - genetics ; Dementia disorders ; Female ; Gene mapping ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Variation ; Glycine ; Heterozygote ; Humans ; Intrinsically Disordered Proteins - genetics ; intrinsically disordered region ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Middle Aged ; Myeloid cells ; Neurodegenerative diseases ; Open Reading Frames - genetics ; Pedigree ; Phenotype ; Protein Transport ; Receptor mechanisms ; Receptors, Immunologic - genetics ; Receptors, Immunologic - metabolism ; Signal Transduction ; Structure-function relationships ; TREM2 ; Tryptophan ; Whole Exome Sequencing
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
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  • 8
    Language: English
    In: Cold Spring Harbor molecular case studies, 2019-12, Vol.5 (6), p.a004465
    Description: Infants suffering from life-threatening apnea, stridor, cyanosis, and increased muscle tone may often be misdiagnosed with infantile seizures and inappropriately treated because of lack and delay in genetic diagnosis. Here, we report a patient with increased muscle tone after birth and hypertonic attacks with life-threatening apnea but no epileptiform patterns in EEG recordings. We identified novel compound heterozygous variants in (NM_004211.4:c.[1429T 〉 C];[1430delC]) by trio whole-exome sequencing, containing a base deletion inherited by the asymptomatic mother leading to a frameshift (c.1430delC, p.Ser477PhefsTer9) and a de novo base exchange leading to an amino acid change (c.1429T 〉 C, p.Ser477Pro). To date, there are four known disease-associated genes for primary hyperekplexia, all of which are involved in the functioning of glycinergic synapses. encodes the sodium- and chloride-dependent glycine transporter 2 (GlyT2), which recaptures glycine, a major inhibitory transmitter in the brainstem and spinal cord. The diagnosis altered the patient's medical care to his benefit because mutations with rather benign courses of hyperekplexia may be spared of needless pharmacotherapy. Symptoms eventually decreased in frequency until about once in 2 mo at 2 yr age. We present the first report of halting hyperekplexia episodes by maternal soothing in multiple instances. We highlight the importance of clarifying the genetic diagnosis by rapid next-generation sequencing techniques in this group of infantile apneic attacks with hyperekplexia due to the broad differential diagnoses.
    Subject(s): Amino acids ; Apnea ; apneic episodes in infancy ; Benign ; Brain stem ; Cyanosis ; Diagnosis ; Drug therapy ; EEG ; Epilepsy ; equinovarus deformity ; exaggerated startle response ; Gene deletion ; Gene sequencing ; Genetic screening ; Glycine ; Glycine transporter ; Infants ; Muscles ; Mutation ; Next-generation sequencing ; Seizures ; Signs and symptoms ; Sodium ; Spinal cord ; Startle response ; Synapses ; Transporter
    ISSN: 2373-2865
    E-ISSN: 2373-2873
    Source: PubMed Central
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  • 9
    Language: English
    In: Clinical epigenetics, 2019-11-27, Vol.11 (1), p.164
    Description: Background Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p(Sidak) = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p(Sidak) = 4.01E-04), RHBDF2 (- 3.45% UC, p(Sidak) = 4.85E-06), and C3 (- 1.20% UC, p(Sidak) = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p(Sidak) = 7.14E-04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.
    Subject(s): 5-HYDROXYMETHYLCYTOSINE ; 5-Methylcytosine - analogs & derivatives ; 5-Methylcytosine - analysis ; 5-Methylcytosine - blood ; 5-Methylcytosine - metabolism ; Advertising executives ; Age of Onset ; Aged ; Aged, 80 and over ; Alzheimer Disease - genetics ; Alzheimer's disease ; Biotechnology industry ; Blood ; Book publishing ; Brain ; Brain Chemistry ; Brain research ; COGNITION ; Comparative analysis ; Cytosine ; DEMENTIA ; Dementia disorders ; Demographics ; Deoxyribonucleic acid ; Development and progression ; Disease Progression ; DNA ; DNA hydroxymethylation ; DNA Methylation ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Female ; Gene expression ; Genes ; Genetics & Heredity ; GENOME-WIDE ASSOCIATION ; Genomes ; Genomics ; Geriatrics ; GLOBAL CHANGES ; HEALTH ; Humans ; HYDROXYMETHYLATION ; Intracellular Signaling Peptides and Proteins - genetics ; Life Sciences & Biomedicine ; Male ; Methylation ; Middle temporal gyrus ; Neurodegenerative diseases ; Oncology ; OXYTOCIN ; Oxytocin - genetics ; Pyrimidines ; Receptors, Nicotinic - genetics ; ROLES ; Science & Technology ; Studies ; Temporal gyrus ; Temporal Lobe - chemistry
    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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  • 10
    Language: English
    In: Immunogenetics (New York), 2017-04-06, Vol.69 (6), p.359-369
    Description: Mast cell activation syndrome (MCAS) and systemic mastocytosis (SM) are two clinical systemic mast cell activation disease variants. Few studies to date have investigated the genetic basis of MCAS. The present study had two aims. First, to investigate whether peripheral blood leukocytes from MCAS patients also harbor somatic mutations in genes implicated in SM using next-generation sequencing (NGS) technology and a relatively large MCAS cohort. We also addressed the question, whether some of the previously as somatic reported mutations are indeed germline mutations. Second, to identify germline mutations of relevance to MCAS pathogenesis. Here, mutation frequency in the present MCAS cohort was compared to that in public- and in-house databases in the case of frequent variants, and co-segregation was investigated in multiply affected families in the case of rare variants (allele frequency 〈 1%). MCAS diagnoses were assigned according to current criteria. Twenty five candidate genes were selected on the basis of published findings for SM. NGS was performed using a 76kbp custom designed Agilent SureSelect Target Enrichment and an Illumina Hiseq2000 2x100bp sequencing run. NGS revealed 67 germline mutations. No somatic mutations were detected. None of the germline mutations showed unequivocal association with MCAS. Failure to detect somatic mutations was probably attributable to the dilution of mutated mast cell DNA in normal leukocyte DNA. The present exploratory association findings suggest that some of the detected germline mutations may be functionally relevant and explain familial aggregation. Independent replication studies are therefore warranted.
    Subject(s): Activation analysis ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Agglomeration ; Alleles ; Allergology ; Amino Acid Substitution ; Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Blood ; Cell activation ; Cell Biology ; Customization ; Deoxyribonucleic acid ; Dilution ; DNA ; DNA Mutational Analysis ; Female ; Gene Frequency ; Gene Function ; Gene mutations ; Gene sequencing ; Genes ; Genetic aspects ; Genome-Wide Association Study ; Genomics - methods ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing ; Human Genetics ; Humans ; Immunology ; Leukocytes ; Leukocytes - metabolism ; Male ; Mastocytosis ; Mastocytosis - diagnosis ; Mastocytosis - genetics ; Medical research ; Medicine, Experimental ; Middle Aged ; Mutation ; Original Article ; Pathogenesis ; Patients ; Pedigree ; Peripheral blood ; Phenotype ; Polymorphism, Single Nucleotide ; Profiling ; Studies ; Syndrome ; Young Adult
    ISSN: 0093-7711
    E-ISSN: 1432-1211
    Source: Alma/SFX Local Collection
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