Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

• MeSH
• bipolární porucha genetika   MeSH
• celogenomová asociační studie * MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genom lidský MeSH
• hlavní histokompatibilní komplex genetika   MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• lokus kvantitativního znaku genetika   MeSH
• multifaktoriální dědičnost genetika   MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. METHODS: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. RESULTS: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. CONCLUSION: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

• MeSH
• dospělí MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• fosfohydroláza PTEN genetika   metabolismus   MeSH
• germinální a embryonální nádory genetika   patologie   MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA metody   MeSH
• nádory vaječníků genetika   patologie   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• sekvenování exomu metody   MeSH
• signální transdukce genetika   MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0.7 and 2.5 Mb at two of the breakpoints in 1q24.3 and 6q24.1-q24.2, respectively, which could explain most symptoms of the patient. Subsequent whole-genome mate-pair sequencing confirmed the chromothriptic nature of the rearrangement. The four participating chromosomes were broken into 29 segments longer than 1 kb. Sanger sequencing of all breakpoint junctions revealed additional complexity compatible with the involvement of different repair pathways. We observed translocation of a 33 bp long DNA fragment, which may have implications for the definition of the lower size limit of structural variants. Our observations and literature review indicate that even very small fragments from shattered chromosomes can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly.

• MeSH
• chromothripsis * MeSH
• DNA genetika   MeSH
• dospělí MeSH
• karyotyp MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mladiství MeSH
• novorozenec MeSH
• oprava DNA * MeSH
• předškolní dítě MeSH
• sekvence nukleotidů MeSH
• zárodečné buňky metabolismus   MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Monoclonal gammopathy of undetermined significance is a pre-malignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS gene mutations, little is known about the molecular mechanism of malignant transformation. We performed whole exome sequencing together with comparative genomic hybridization plus single nucleotide polymorphism array analysis in 33 flow-cytometry-separated abnormal plasma cell samples from patients with monoclonal gammopathy of undetermined significance to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations and copy-number alterations were present in 97.0% and in 60.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in monoclonal gammopathy of undetermined significance than in myeloma (P<10-4) and we identified six genes that were significantly mutated in myeloma (KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB) within the monoclonal gammopathy of undetermined significance dataset. We also found a positive correlation with increasing chromosome changes and somatic gene mutations. IGH translocations, comprising t(4;14), t(11;14), t(14;16) and t(14;20), were present in 27.3% of cases and in a similar frequency to myeloma, consistent with the primary lesion hypothesis. MYC translocations and TP53 deletions or mutations were not detected in samples from patients with monoclonal gammopathy of undetermined significance, indicating that they may be drivers of progression to myeloma. Data from this study show that monoclonal gammopathy of undetermined significance is genetically similar to myeloma, however overall genetic abnormalities are present at significantly lower levels in monoclonal gammopathy of undetermined significant than in myeloma.

• MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mnohočetný myelom genetika   patologie   MeSH
• monoklonální gamapatie nejasného významu genetika   patologie   MeSH
• nádorové proteiny genetika   MeSH
• průtoková cytometrie MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Chromosome architecture needs to be investigated in relation with the chemical function of DNA. The kinetics of gene expression, DNA replication, and repair are driven by the mechanisms by which a functional nuclear protein finds its substrate in the nucleus. Single-particle tracking (SPT) is a method to quantify fluorescent molecules dynamics from the tracks of the single molecules recorded by high-resolution microscopes. SPT offers direct observation of the movement and single-molecule resolution. Usually SPT is performed on membranes because of higher contrast. Here, we introduce a novel method to record the trajectories of weakly fluorescent molecules in the nucleus of living cells. I-SPT uses some specific detection and analysis tools to enable the computation of reliable statistics on nuclear particle movement.

• MeSH
• buněčné jádro metabolismus   MeSH
• buněčné linie MeSH
• lidé MeSH
• lidské chromozomy genetika   ultrastruktura   MeSH
• počítačové zpracování obrazu MeSH
• replikace DNA MeSH
• zobrazení jednotlivé molekuly metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.

• MeSH
• akutní megakaryoblastická leukemie genetika   mortalita   MeSH
• chromozomální aberace * MeSH
• dítě MeSH
• genová přestavba * MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mladiství MeSH
• nádorové proteiny genetika   MeSH
• předškolní dítě MeSH
• rizikové faktory MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Dicentric chromosomes (DCs) have been described in many hematological diseases, including acute myeloid leukemia (AML). They are markers of cancer and induce chromosomal instability, leading to the formation of other chromosomal aberrations and the clonal evolution of pathological cells. Our knowledge of the roles and behavior of human DCs is often derived from studies of induced DCs and cell lines. It is difficult to identify all the DCs in the karyotypes of patients because of the limitations of metaphase cytogenetic methods. The aim of this study was to revise the karyotypes of 20 AML patients in whom DCs were found with conventional G-banding or multicolor fluorescence in situ hybridization (mFISH) with (multi)centromeric probes and to characterize the DCs at the molecular cytogenetic level. FISH analyses confirmed 23 of the 29 expected DCs in 18 of 20 patients and identified 13 others that had not been detected cytogenetically. Fourteen DCs were altered by other chromosomal changes. In conclusion, karyotypes with DCs are usually very complex, and we have shown that they often contain more than one DC, which can be missed with conventional or mFISH methods. Our study indicates an association between number of DCs in karyotype and very short survival of patients.

• MeSH
• abnormální karyotyp * MeSH
• akutní myeloidní leukemie genetika   mortalita   MeSH
• hybridizace in situ fluorescenční * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• míra přežití MeSH
• nádorové buněčné linie MeSH
• přežití po terapii bez příznaků nemoci MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

AIMS: The primaryAIM was to investigate variables affecting compliance in pregnant women recommended for genetic consultation for abnormal screening test results, family predisposition or medical history. Our main focus was on a women's knowledge of particular screening tests, their initial feelings and changes in these feeling with time, as well as variables relevant to further decision making. METHODS: We used an anonymous questionnaire based on previous qualitative research. The questions were formulated by a medical geneticist, and the questionnaires were distributed prior to prenatal screening tests performed by doctors or trained nurses. The research cohort consisted of 271 women aged 16-42 years. Six hypotheses were tested using the statistical programme STATISTICA; significance levels were set to P<0.05. RESULTS: The questionnaire results showed insufficient knowledge. The women were confused about invasive, screening and ultrasound tests. Genetic test recommendation was largely associated with stress in these patients. Between recommendation and consultation, the women mostly looked for support from their partners. There was a surprisingly low percentage of women who looked for help from their medical specialists and a surprisingly high percentage of those who did not seek any help at all. CONCLUSION: Women's distress can be reduced if the information about recommended genetic consultation is conveyed correctly and this can also help them make the right informed decision about their future course of action.

• MeSH
• dospělí MeSH
• genetické testování MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci plodu diagnóza   genetika   MeSH
• prenatální diagnóza metody   MeSH
• prevalence MeSH
• průzkumy a dotazníky * MeSH
• rozhodování * MeSH
• těhotenství MeSH
• vrozené vady diagnóza   epidemiologie   genetika   MeSH
• zdraví - znalosti, postoje, praxe * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

• MeSH
• aneuploidie MeSH
• asistovaná reprodukce MeSH
• chromozomální aberace embryologie   MeSH
• ektogeneze MeSH
• embryonální vývoj * genetika   MeSH
• genetické testování využití   MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mutace * genetika   MeSH
• párování chromozomů MeSH
• preimplantační diagnóza metody   MeSH
• přenos embrya MeSH
• ztráta embrya genetika   MeSH
• Check Tag
• lidé MeSH

The significance of chromosomal translocations (CTRAs) and karyotype complexity (KC) in chronic lymphocytic leukemia (CLL) remains uncertain. To gain insight into these issues, we evaluated a series of 1001 CLL cases with reliable classic cytogenetic data obtained within 6 months from diagnosis before any treatment. Overall, 320 cases were found to carry >= 1 CTRAs. The most frequent chromosome breakpoints were 13q, followed by 14q, 18q, 17q, and 17p; notably, CTRAs involving chromosome 13q showed a wide spectrum of translocation partners. KC (>= 3 aberrations) was detected in 157 cases and significantly (P < 0.005) associated with unmutated IGHV genes and aberrations of chromosome 17p. Furthermore, it was identified as an independent prognostic factor for shorter time-to-first-treatment. CTRAs were assigned to two categories (i) CTRAs present in the context of KC, often with involvement of chromosome 17p aberrations, occurring mostly in CLL with unmutated IGHV genes; in such cases, we found that KC rather than the presence of CTRAs per se negatively impacts on survival; (ii) CTRAs in cases without KC, having limited if any impact on survival. On this evidence, we propose that all CTRAs in CLL are not equivalent but rather develop by different processes and are associated with distinct clonal behavior. Copyright © 2013 Wiley Periodicals, Inc.

• MeSH
• body zlomu chromozomu MeSH
• buněčné kultury metody   MeSH
• chromozomální aberace MeSH
• chromozomální delece MeSH
• chronická lymfatická leukemie * genetika   patologie   MeSH
• hybridizace in situ fluorescenční MeSH
• interfáze MeSH
• Kaplanův-Meierův odhad MeSH
• karyotypizace metody   MeSH
• lidé MeSH
• lidské chromozomy genetika   ultrastruktura   MeSH
• nádorové buňky kultivované MeSH
• přestavba genů pro těžké řetězce B-lymfocytů MeSH
• proporcionální rizikové modely MeSH
• translokace genetická * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH