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  • 1
    Language: English
    In: Blood, 2017-11-02, Vol.130 (18), p.2027-2031
    Description: The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19–) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19– malignant progenitor cells. We present 2 BCR-ABL1 fusion–positive BCP-ALL patients with CD19– myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1–positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19– precursors should be targeted to avoid CD19– relapses in patients with BCR-ABL1–positive ALL. •BCR-ABL1–positive cells outside the B-lineage compartment are found in 40% of adult patients with BCR-ABL1–positive BCP-ALL.•Selection of preexisting CD19– subclones is a potential source of tumor escape after CD19-targeted therapies in adult Philadelphia chromosome–positive ALL.
    Subject(s): Adult ; Antibodies, Bispecific - therapeutic use ; Blast Crisis - pathology ; Brief Report ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl - metabolism ; Hematopoietic Stem Cells - metabolism ; Humans ; Immunophenotyping ; Lymphoid Neoplasia ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: Alma/SFX Local Collection
    Source: American Society of Hematology
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  • 2
    Language: English
    In: Breast cancer research and treatment, 2019-02-06, Vol.175 (1), p.217-228
    Description: Purpose To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. Results A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9–93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6–85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6–91.7), p  〈 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8–62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3–6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. Conclusions High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.
    Subject(s): Age ; BRCA1 protein ; BRCA2 protein ; Breast cancer ; Cancer ; Clinical Trial ; Consortia ; Diagnosis ; Genetic aspects ; Health aspects ; Invasiveness ; Life Sciences & Biomedicine ; Magnetic resonance imaging ; Medicine ; Medicine & Public Health ; Oncology ; Ovarian cancer ; Risk factors ; Risk groups ; Science & Technology ; Surveillance
    ISSN: 0167-6806
    E-ISSN: 1573-7217
    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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  • 3
    Language: English
    In: Nature genetics, 2014-12, Vol.46 (12), p.1327-1332
    Description: Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
    Subject(s): Amino Acid Sequence ; Animals ; Codon, Nonsense ; Cohort Studies ; Comparative Genomic Hybridization ; Convulsions & seizures ; Epilepsy ; Epilepsy - genetics ; Exome ; Female ; Gene Deletion ; Gene mutations ; Genetic aspects ; Genetic Linkage ; Genetics ; Human health and pathology ; Humans ; Identification and classification ; In Situ Hybridization, Fluorescence ; Life Sciences ; Male ; Membrane proteins ; Molecular Sequence Data ; Mutation ; Neurobiology ; Neurons and Cognition ; Pedigree ; Phenotype ; Polymorphism, Single Nucleotide ; Properties ; Risk factors ; Seizures (Medicine) ; Seizures, Febrile - genetics ; Sequence Analysis, DNA ; Syntaxin 1 - genetics ; Temperature ; Zebrafish
    ISSN: 1061-4036
    E-ISSN: 1546-1718
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: European journal of human genetics : EJHG, 2009, Vol.17 (5), p.582-590
    Description: The Prader-Willi syndrome (PWS) is caused by a 5-6 Mbp de novo deletion on the paternal chromosome 15, maternal uniparental disomy 15 or an imprinting defect. All three lesions lead to the lack of expression of imprinted genes that are active on the paternal chromosome only: MKRN3, MAGEL2, NDN, C15orf2, SNURF-SNRPN and more than 70 C/D box snoRNA genes (SNORDs). The contribution to PWS of any of these genes is unknown, because no single gene mutation has been described so far. We report on two patients with PWS who have an atypical deletion on the paternal chromosome that does not include MKRN3, MAGEL2 and NDN. In one of these patients, NDN has a normal DNA methylation pattern and is expressed. In another patient, the paternal alleles of these genes are deleted as the result of an unbalanced translocation 45,X,der(X)t(X;15)(q28;q11.2). This patient is obese and mentally retarded, but does not have PWS. We conclude that a deficiency of MKRN3, MAGEL2 and NDN is not sufficient to cause PWS.
    Subject(s): Adolescent ; Adult ; atypical deletions ; Biological and medical sciences ; Child ; Child, Preschool ; Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 15 - genetics ; Classical genetics, quantitative genetics, hybrids ; DNA Methylation ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression ; General aspects. Genetic counseling ; Genetics of eukaryotes. Biological and molecular evolution ; Human ; Humans ; imprinting ; Karyotyping ; Male ; Medical genetics ; Medical sciences ; Metabolic diseases ; Molecular and cellular biology ; Nerve Tissue Proteins - genetics ; Nuclear Proteins - genetics ; Obesity ; Prader-Willi Syndrome - genetics ; Prader-Willi Syndrome - pathology ; Prader–Willi syndrome ; Proteins - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleoproteins - genetics
    ISSN: 1018-4813
    E-ISSN: 1476-5438
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Journal of medical genetics, 2021-06, Vol.58 (6), p.415-421
    Description: BackgroundWe describe two unrelated patients who display similar clinical features including telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease.MethodsWe performed trio whole exome sequencing and functional analysis using in vitro kinase assays with recombinant proteins.ResultsWe identified two different de novo mutations in protein kinase D1 (PRKD1, NM_002742.2): c.1774G〉C, p.(Gly592Arg) and c.1808G〉A, p.(Arg603His), one in each patient. PRKD1 (PKD1, HGNC:9407) encodes a kinase that is a member of the protein kinase D (PKD) family of serine/threonine protein kinases involved in diverse cellular processes such as cell differentiation and proliferation and cell migration as well as vesicle transport and angiogenesis. Functional analysis using in vitro kinase assays with recombinant proteins showed that the mutation c.1808G〉A, p.(Arg603His) represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The mutation c.1774G〉C, p.(Gly592Arg) in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.ConclusionThe present cases represent a syndrome, which associates symptoms from several different organ systems: skin, teeth, bones and heart, caused by heterozygous de novo mutations in PRKD1 and expands the clinical spectrum of PRKD1 mutations, which have hitherto been linked to syndromic congenital heart disease and limb abnormalities.
    Subject(s): Adolescent ; Age ; Angiogenesis ; Brachydactyly ; Brachydactyly - enzymology ; Brachydactyly - genetics ; Cardiovascular disease ; Cell differentiation ; Cell migration ; Congenital diseases ; Coronary artery disease ; Dysplasia ; Ectodermal Dysplasia - enzymology ; Ectodermal Dysplasia - genetics ; Enamel ; Enzymes ; Erythema ; Female ; Hair ; Heart diseases ; HEK293 Cells ; Humans ; Kinases ; Male ; Mutation ; Pathogenesis ; Patients ; Phosphorylation ; Protein kinase ; Protein Kinase C - genetics ; Proteins ; Serine ; Skin ; Syndrome ; Telangiectasis - enzymology ; Telangiectasis - genetics ; Threonine ; Whole Exome Sequencing ; Young Adult
    ISSN: 0022-2593
    E-ISSN: 1468-6244
    Source: Hellenic Academic Libraries Link
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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
    In: PloS one, 2013, Vol.8 (10), p.e76953-e76953
    Description: NLRP7 is a maternal effect gene as maternal mutations in this gene cause recurrent hydatidiform moles, spontaneous abortions and stillbirths, whereas live births are very rare. We have studied a patient with multiple anomalies born to a mother with a heterozygous NLRP7 mutation. By array-based CpG methylation analysis of blood DNA from the patient, his parents and 18 normal controls on Illumina Infinium HumanMethylation27 BeadChips we found that the patient had methylation changes (delta ß ≥ 0.3) at many imprinted loci as well as at 87 CpGs associated with 85 genes of unknown imprinting status. Using a pseudoproband (permutation) approach, we found methylation changes at only 7-24 CpGs (mean 15; standard deviation 4.84) in the controls. Thus, the number of abberantly methylated CpGs in the patient is more than 14 standard deviations higher. In order to identify novel imprinted genes among the 85 conspicuous genes in the patient, we selected 19 (mainly hypomethylated) genes for deep bisulfite amplicon sequencing on the ROCHE/454 Genome Sequencer in the patient and at least two additional controls. These controls had not been included in the array analysis and were heterozygous for a single nucleotide polymorphism at the test locus, so that allele-specific DNA methylation patterns could be determined. Apart from FAM50B, which we proved to be imprinted in blood, we did not observe allele-specific DNA methylation at the other 18 loci. We conclude that the patient does not only have methylation defects at imprinted loci but (at least in blood) also an excess of methylation changes at apparently non-imprinted loci.
    Subject(s): Adaptor Proteins, Signal Transducing - genetics ; Alleles ; Analysis ; Base Sequence ; Binding sites ; Bisulfite ; Blood ; CpG islands ; CpG Islands - genetics ; Defects ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; Epigenetics ; Female ; Gene expression ; Gene sequencing ; Genes ; Genetic aspects ; Genetic Diseases, Inborn - blood ; Genetic Diseases, Inborn - genetics ; Genetic Loci - genetics ; Genomes ; Genomic Imprinting - genetics ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Imprinting ; Loci ; Male ; Medical research ; Medicine, Experimental ; Methylation ; Mutation ; Parents ; Permutations ; Polymorphism ; Sequence Analysis, DNA ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Sulfites ; Sulfites - chemistry
    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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  • 8
    Language: English
    In: American journal of human genetics, 2013-07-11, Vol.93 (1), p.67-77
    Description: Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.
    Subject(s): Animals ; Cardiomyopathy ; Cardiomyopathy, Dilated - genetics ; Cardiomyopathy, Dilated - pathology ; Cardiovascular disease ; Case-Control Studies ; Causes of ; Cell Proliferation ; Chromosome Deletion ; Chromosome Disorders - genetics ; Chromosome Mapping - methods ; Chromosomes, Human, Pair 1 - genetics ; Comparative Genomic Hybridization ; DNA-Binding Proteins - genetics ; Exons ; Frameshift Mutation ; Gene mutations ; Genetic aspects ; Genomics ; Health aspects ; Heart diseases ; Humans ; Isolated Noncompaction of the Ventricular Myocardium - genetics ; Mutation ; Mutation, Missense ; Myocardial Contraction ; Myocytes, Cardiac ; Physiological aspects ; Research ; Transcription factors ; Transcription Factors - genetics ; Youth participation ; Zebrafish ; Zebrafish - embryology ; Zebrafish - genetics
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Cell Press Collection [ECCPC]
    Source: PubMed Central
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  • 9
    Language: English
    In: American journal of human genetics, 2019-05-02, Vol.104 (5), p.985-989
    Description: We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C〉T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.
    Subject(s): agenesis ; Amino Acid Sequence ; Animals ; development ; Developmental Disabilities - etiology ; Developmental Disabilities - pathology ; diabetes ; Embryo, Mammalian - metabolism ; Embryo, Mammalian - pathology ; Female ; genetics ; Genetics & Heredity ; Holoprosencephaly - etiology ; Holoprosencephaly - pathology ; Humans ; Infant ; Infant, Newborn ; Infant, Newborn, Diseases - etiology ; Infant, Newborn, Diseases - pathology ; Life Sciences & Biomedicine ; Male ; Mice ; Mice, Knockout ; Mutation ; neonatal ; Nervous System Diseases - etiology ; Nervous System Diseases - pathology ; neurological ; pancreas ; Pancreas - abnormalities ; Pancreas - pathology ; Pancreatic Diseases - congenital ; Pancreatic Diseases - etiology ; Pancreatic Diseases - pathology ; Pedigree ; Phenotype ; Report ; Science & Technology ; Sequence Homology ; Syndrome ; Transcription Factors - genetics
    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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  • 10
    Language: English
    In: Archives of gynecology and obstetrics, 2017-10-09, Vol.297 (1), p.147-152
    Description: Purpose Mutations in the CDH1 gene are linked both to diffuse gastric cancer and invasive lobular carcinoma (ILC). A high mutation rate is found in families fulfilling the diagnostic criteria for hereditary diffuse gastric cancer. Aim of this study was to clarify whether or not there is a significant contribution of CDH1 mutations in hereditary breast-/ovarian cancer (HBOC). Methods Ninety-seven unrelated probands fulfilling the diagnostic criteria for HBOC (96 affected, 1 unaffected) but tested negative for pathogenic BRCA1/2 mutations were screened for CDH1 mutations by denaturing high performance liquid chromatography (DHPLC) and subsequent Sanger sequencing of suspicious and positive DHPLC results. Results In total, we found two potentially pathogenic CDH1 alterations, c.1774G 〉 A, pAla592Thr, and c.2512 A 〉 G, p.Ser838Gly, classified as variants of unknown significance according to ClinVar. In addition, we detected a high number of known CDH1 polymorphisms ( n  = 62), some of them more frequent in patients with lobular (55%) than in those with invasive ductal carcinoma (27%). Conclusion Although none of the probands studied carried a clearly pathogenic CDH1 mutation, CDH1 could be considered a potential breast cancer gene, esp. for ILC worth including it in the NGS (next generation sequencing) HBOC panel.
    Subject(s): Adult ; Antigens, CD - metabolism ; BRCA1 Protein - metabolism ; BRCA2 Protein - metabolism ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cadherins - metabolism ; Cohort Studies ; DNA sequencing ; Early Detection of Cancer ; Endocrinology ; Female ; Genetic aspects ; Genetic Predisposition to Disease ; Gynecologic Oncology ; Gynecology ; High performance liquid chromatography ; Human Genetics ; Humans ; Medicine ; Medicine & Public Health ; Mutation ; Nucleotide sequencing ; Obstetrics/Perinatology/Midwifery ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Stomach cancer
    ISSN: 0932-0067
    E-ISSN: 1432-0711
    Source: Alma/SFX Local Collection
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