1st English edition 275 stran : ilustrace ; 30 cm
The university textbook focuses on medical genetics. Intended for professional use.
- MeSH
- lékařská genetika MeSH
- Konspekt
- Obecná genetika. Obecná cytogenetika. Evoluce
- Učební osnovy. Vyučovací předměty. Učebnice
- NLK Obory
- genetika, lékařská genetika
- NLK Publikační typ
- učebnice vysokých škol
- kolektivní monografie
Cíl: Shrnutí poznatků v oblasti karcinomu ovaria a genetické dispozice. Výsledky: Nádory ovarií jsou obvykle dia gnostikovány v pokročilých stadiích nemoci a prognóza těchto nemocných je všeobecně špatná. Pětileté celkové přežití bez ohledu na histopatologický typ nádoru se pohybuje kolem 44 %. Na vzniku epiteliálního ovariálního nádoru se majoritně podílejí germinální mutace způsobující dědičné nádorové syndromy. Nejčastější je dědičný nádorový syndrom prsu a vaječníku, který je zapříčiněn germinální mutací v tumor supresorových genech BRCA1 a BRCA2. Je známo i několik dalších tumor supresorových genů a onkogenů, které jsou asociovány s ovariálními nádory a způsobují jiné typy nádorových syndromů. Z dědičných nádorových syndromů je to např. Lynchův syndrom, Peutz-Jegersův syndrom, Gorlinův syndrom, Li-Fraumeniho syndrom a další. Indikaci ke genetickému vyšetření germinálních mutací dává klinický genetik na základě doporučení ošetřujícího lékaře. V současné době je každý ovariální nádor, primární peritoneální nádor a nádor tuby diagnostikovaný v jakémkoliv věku indikován ke genetickému vyšetření. Závěr: Časná identifikace genů dědičných nádorových syndromů díky rychle se rozvíjejícím molekulárně genetickým metodám představuje důležitý krok k personalizované léčbě nádorů ovaria a k preventivním opatřením u rizikových rodin. Důležité je si zároveň uvědomit, že negativní výsledek molekulárně genetického vyšetření není vyloučením genetického rizika.
Objective: Summary of knowledge in the field of ovarian cancer and genetic predisposition. Results: Ovarian tumors are usually diagnosed at advanced stages of the disease and the prognosis for these patients is generally poor. The 5-year overall survival rate, regardless of the histopathological type of tumor, is around 44%. Germline mutations causing hereditary tumor syndromes are predominantly involved in the development of epithelial ovarian tumors. The most common is hereditary breast and ovarian cancer syndrome, which is caused by germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Several other tumor suppressor genes and oncogenes are known to be associated with ovarian tumors and cause other types of tumor syndromes. Inherited tumor syndromes include Lynch syndrome, Peutz-Jegers syndrome, Gorlin syndrome, Li-Fraumeni syndrome and others. The indication for genetic examination of germline mutations is given by a clinical geneticist on the basis of the recommendation of the attending physician. At present, every ovarian tumor, primary peritoneal tumor and tube tumor diagnosed at any age is indicated for genetic testing. Conclusion: Early identification of genes for hereditary cancer syndromes, thanks to rapidly developing molecular genetic methods, is an important step towards personalized treatment of ovarian cancer and preventive measures in families at risk. It is also important to note that a negative molecular genetic test result does not exclude genetic risk.
The deficiency of natural anticoagulants-antithrombin (AT), protein C (PC), and protein S (PS)-is a highly predisposing factor for thrombosis, which is still underdiagnosed at the genetic level. We aimed to establish and evaluate an optimal diagnostic approach based on a high-throughput sequencing platform suitable for testing a small number of genes. A fast, flexible, and efficient method involving automated amplicon library preparation and target sequencing on the Ion Torrent platform was optimized. The cohort consisted of a group of 31 unrelated patients selected for sequencing due to repeatedly low levels of one of the anticoagulant proteins (11 AT-deficient, 13 PC-deficient, and 7 PS-deficient patients). The overall mutation detection rate was 67.7%, highest in PC deficiency (76.9%), and six variants were newly detected-SERPINC1 c.398A > T (p.Gln133Leu), PROC c.450C > A (p.Tyr150Ter), c.715G > C (p.Gly239Arg) and c.866C > G (p.Pro289Arg), and PROS1 c.1468delA (p.Ile490fs) and c.1931T > A (p.Ile644Asn). Our data are consistent with those of previous studies, which mostly used time-consuming Sanger sequencing for genotyping, and the indication criteria for molecular genetic testing were adapted to this process in the past. Our promising results allow for a wider application of the described methodology in clinical practice, which will enable a suitable expansion of the group of indicated patients to include individuals with severe clinical findings of thrombosis at a young age. Moreover, this approach is flexible and applicable to other oligogenic panels.
- Publikační typ
- časopisecké články MeSH
Parkinsonism belongs to the most common neurodegenerative disease. Genetic predisposition could be one of the significant risk factor for disease development. It has been described higher prevalence of parkinsonism in large pedigree from southeastern Moravia region. The study aims were to select accessible subfamily trios from the pedigree suitable for segregation genetic analyses to perform whole exome sequencing (WES) in trio individuals and further to evaluate genetic variants in the each trio. We used IonTorrent platform for WES for five subfamily trios (1-5). Each trio included two affected and one healthy person (as control). Found variants were filtered with respect to MAF < 1% (minor allele frequency), variants effect (based on prediction tools) and disease filter (Parkinsonism responsible genes). Finally, the variants from each trio were assessed with respect to the presence in the patients. There were found no one founder mutation in the subfamilies from the pedigree. Trio 1 shares two variants with trio 2:MC1R:c.322G > A (p.A108T) and MTCL1:c.1445C > T (p.A482V), trio 3 shares two variants with trio 5: DNAJC6:c.1817A > C (p.H606P) and HIVEP3:c.3856C > A (p.R1286W). In trios 4 and 5, there were found two variants in gene CSMD1:c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) respectively. As the most potentially damaging, we evaluated the non-shared variant SLC18A2:c.583G > A (p.G195S). The variant could affect dopamine transport in dopaminergic neurons. The study of the parkinsonism genetic background in isolated Moravian population suggested that there could be significant accumulation of many risk genetic factors. For verification of the variants influence, it would be appropriate to perform a more extensive population study and suitable functional analysis.
- Publikační typ
- časopisecké články MeSH
SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.
Parkinson's disease and parkinsonism are relatively common neurodegenerative disorders. This study aimed to assess potential genetic risk factors of haplotypes in genes associated with parkinsonism in a population in which endemic parkinsonism and atypical parkinsonism have recently been found. The genes ADH1C, EIF4G1, FBXO7, GBA, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PINK1 PLA2G6, SNCA, UCHL1, and VPS35 were analyzed in 62 patients (P) and 69 age-matched controls from the researched area (C1). Variants were acquired by high-throughput sequencing using Ion Torrent workflow. As another set of controls, the whole genome sequencing data from 100 healthy non-related individuals from the Czech population were used (C2); the results were also compared with the Genome Project data (C3). We observed shared findings of four intron (rs11564187, rs36220738, rs200829235, and rs3789329) and one exon variant (rs33995883) in the LRRK2 gene in six patients. A comparison of the C1-C3 groups revealed significant differences in haplotype frequencies between ratio of 2.09 for C1, 1.65 for C2, and 6.3 for C3, and odds ratios of 13.15 for C1, 2.58 for C2, and 7.6 for C3 were estimated. The co-occurrence of five variants in the LRRK2 gene (very probably in haplotype) could be an important potential risk factor for the development of parkinsonism, even outside the recently described pedigrees in the researched area where endemic parkinsonism is present.
- Publikační typ
- časopisecké články MeSH
AIMS: Turner syndrome is the only chromosome monosomy that is postnatally compatible with life. The reported incidence of TS is 1 in 2500 liveborn girls. The phenotype of these girls is highly variable, with cardiac abnormalities being life-threatening defects. The aim of the study was to reveal the possible influence of the parental origin of the X chromosome in these patients on a selected phenotype that is associated with Turner syndrome. Selected symptoms and parameters were: a bicuspid aortic valve, aortic coarctation, lymphoedema, pterygium colli, coeliac disease, thyroiditis, otitis media, diabetes mellitus 2, renal abnormalities, spontaneous puberty, and IVF. METHODS: The X chromosome haplotype was determined for a group of 45,X patients verified by native FISH. A molecular diagnostic method based on the detection of different lengths of X chromosome-linked STR markers using the Argus X-12 QS kit was used to determine the X haplotype. RESULTS: Our results, analysed by Fisher's exact (factorial) test, suggest independence between the maternal/paternal origin of the inherited X chromosome and the presence of the anomalies that were studied (P=1 to P=0.34). CONCLUSION: In the group of 45,X patients, who were precisely selected by means of the native FISH method, no correlation was demonstrated with the parental origin of the X chromosome and the observed symptom.
- MeSH
- chromozom X MeSH
- fenotyp MeSH
- haplotypy MeSH
- lidé MeSH
- Turnerův syndrom * genetika MeSH
- vrozené srdeční vady * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hereditary spastic paraplegia (HSP or SPG) is a group of rare upper motor neuron diseases. As some ethnically-specific, disease-causing homozygous variants were described in the Czech Roma population, we hypotesised that some prevalent HSP-causing variant could exist in this population. Eight Czech Roma patients were found in a large group of Czech patients with suspected HSP and were tested using gene panel massively parallel sequencing (MPS). Two of the eight were diagnosed with SPG11 and SPG77, respectively. The SPG77 patient manifests a pure HSP phenotype, which is unusual for this SPG type. Both patients are compound heterozygotes for two different variants in the SPG11 (c.1603-1G>A and del ex. 16-18) and FARS2 (c.1082C>T and del ex.1-2) genes respectively; the three variants are novel. In order to find a potential ethnically-specific, disease-causing variant for HSP, we tested the heterozygote frequency of these variants among 130 anonymised DNA samples of Czech Roma individuals without clinical signs of HSP (HPS-negative). A novel deletion of ex.16-18 in the SPG11 gene was found in a heterozygous state in one individual in the HSP-negative group. Haplotype analysis showed that this individual and the patient with SPG11 shared the same haplotype. This supports the assumption that the identified SPG11 deletion could be a founder mutation in the Czech Roma population. In some Roma patients the disease may also be caused by two different biallelic pathogenic mutations.
- MeSH
- dítě MeSH
- dospělí MeSH
- etnicita genetika MeSH
- fenylalanin-tRNA-ligasa genetika MeSH
- genetická variace genetika MeSH
- heterozygot * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mitochondriální proteiny genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- proteiny genetika MeSH
- rodokmen MeSH
- Romové etnologie genetika MeSH
- spastická paraplegie dědičná diagnóza etnologie genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Trombofilní stavy představují vrozenou nebo získanou predispozici vzniku trombózy v cévním řečišti. Mezi rutinně vyšetřované vrozené trombofilie patří v populaci vysoce frekventní leidenská mutace a mutace v genu protrombinu G20210A. Vrozený deficit antikoagulačních proteinů (proteinu S, proteinu C a antitrombinu III) patří mezi vzácné trombofilie s nižší populační frekvencí, ale vyšším relativním rizikem tromboembolické příhody a je způsobený mutacemi v genech kódujících tyto proteiny. Postup molekulárně genetické analýzy závisí na skutečnosti, zda se jedná o vyhledávání známé, nebo neznámé, případně vzácné varianty. U známých kauzálních variant FV Leiden a protrombinu G20210A využíváme k jejich zachycení běžně metody PCR-RFLP, reverzní Strip Assay®, alelově-specifickou PCR, TaqMan real-time PCR a SNaPshot®. Genetickému testování vzácných variant v antikoagulačních proteinech předchází precizní selekce pacientů. Vhodné je využití metodiky masivního paralelního sekvenování doplněné vyhledáváním větších genových přestaveb metodou MLPA. Tento postup je úspěšně aplikován na našem pracovišti a ve srovnání s běžně užívanou Sangerovou sekvenační metodou nabízí rychlejší odezvu a větší analytickou kapacitu.
Thrombotic states are inherited or acquired predisposition for thrombosis in the human vascular system. Nowadays Leiden mutation and mutation in prothrombin G20210A contributing to congenital thrombophilia are routinely tested. These mutations have a high prevalence in the population. Congenital deficiencies of protein S, protein C and antithrombin III are rare thrombophilia with lower population frequency, but higher risk of thromboembolic event. The genetic causes are mutations in the genes, which encode these proteins. The choice of proper molecular genetic testing depends on the difference in the detection of well-known single nucleotide polymorphism or unknown/rare variant. For the detection of causative variant FV Leiden and prothrombin G20210A are mostly used PCR-RFLP, reverse Strip Assay®, allele-specific PCR, TaqMan real-time PCR and SNaPshot®. Precise patient selection should precede the genetic testing of rare variants in anticoagulant proteins. It is appropriate to use methodology of massive parallel sequencing supplemented by a methodology for the detection of larger gene rearrangements – MLPA. We are successfully employing this approach in our institute. This methodology is faster with larger analytic capacity compared to commonly used direct sequencing by Sanger method
