The discovery of modulators that target cystic fibrosis transmembrane conductance regulator (CFTR) protein has opened the era of CF curative treatment. Although this therapy is termed mutation specific, strikingly a level of therapeutic response differs among patients with the identical CFTR genotype. We presume that the therapeutic response is also affected by non-CFTR genes, called disease modifying. Responsiveness of a CF patient to the modulator therapy is being investigated in vitro by using a intestinal organoids that are obtained from rectal biopsies. The proposed project aims to set organoids from the Czech CF patients who carry the most common CFTR genotype. Modifying genes that can contribute to individualised response will be selected on the grounds of changes in transcriptomic profiles which will be generated from organoids at the extremes of responses to the stimultation with CFTR modulators. Genotyping of SNPs in these genes will follow. The project output is to use organoids and modifying gene genotypes to identify suitable subjects for particular modulator therapy.

Objev modulátorů, které cílí na transmembránový regulátor vodivosti asociovaný s cystickou fibrózou (CFTR), otevřel etapu kauzální léčby CF. I když se tato terapie nazývá mutačně specifická, liší se míra odpovědi na léčbu i mezi těmi pacienty, kteří mají identický CFTR genotyp. Lze tak předjímat, že odpověď k léčbě ovlivňují ještě další geny nad rámec genu CFTR, tzv. geny modifikující onemocnění. Zda bude konkrétní pacient reagovat na léčbu modulátory CFTR, se zkouší in vitro predikovat na modelu intestinálních organoidů, získaných z rektálních biopsií. Navrhovaný projekt počítá s přípravou organoidů od českých pacientů s CF, kteří nesou nejčastější CFTR genotyp. Modifikující geny, které se mohou podílet na individualizované odpovědi k léčbě, vytipujeme na základě rozdílů v transkriptomových profilech, jež budou generovány z organoidů reagujících nejlépe a nejhůře na stimulaci CFTR modulátory. Dále srovnáme polymorfismy těchto genů. Výstupem projektu bude stratifikace pacientů coby vhodných kandidátů k dané léčbě na základě organoidů i znalosti genotypu modifikujících genů.

• Klíčová slova
• cystická fibróza, cystic fibrosis, organoidy, léky modulující CFTR, organoids, CFTR modulator drugs, modifikující geny, modifying genes,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

AIM: To utilize three-dimensional (3D) geometric morphometry for visualization of the level of facial asymmetry in patients with the oculo-auriculo-vertebral spectrum (OAVS). MATERIALS AND METHODS: Three-dimensional facial scans of 25 Czech patients with OAVS were processed. The patients were divided into subgroups according to Pruzansky classification. For 13 of them, second 3D facial scans were obtained. The 3D facial scans were processed using geometric morphometry. Soft tissue facial asymmetry in the sagittal plane and its changes in two time spots were visualized using colour-coded maps with a thermometre-like scale. RESULTS: Individual facial asymmetry was visualized in all patients as well as the mean facial asymmetry for every Pruzansky subgroup. The mean colour-coded maps of type I and type IIA subgroups showed no differences in facial asymmetry, more pronounced asymmetry in the middle and the lower facial third was found between type IIA and type IIB (maximum 1.5 mm) and between type IIB and type III (maximum 2 mm). The degree of intensity facial asymmetry in affected middle and lower facial thirds did not change distinctly during the two time spots in all subgroups. CONCLUSIONS: The 3D geometric morphometry in OAVS patients could be a useful tool for objective facial asymmetry assessment in patients with OAVS. The calculated colour-coded maps are illustrative and useful for clinical evaluation.

• MeSH
• asymetrie obličeje * diagnostické zobrazování   patologie   MeSH
• dítě MeSH
• Goldenharův syndrom * diagnostické zobrazování   patologie   MeSH
• kefalometrie metody   MeSH
• lidé MeSH
• mladiství MeSH
• obličej anatomie a histologie   diagnostické zobrazování   patologie   MeSH
• zobrazování trojrozměrné * metody   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Genová terapie (GT) se postupně stává běžným způsobem léčby. Již není výsadou velkých univerzitních pracovišť, jejichž laboratoře zvládají analytické postupy zaměřené na nukleové kyseliny a jejichž klinické týmy zvládají aplikaci. Původně byla určena pro dědičné choroby, které vzhledem ke svému řídkému výskytu byly označovány jako vzácná onemocnění a GT se dosud uplatňovala jen u dětí, aby působila ještě před rozvojem onemocnění. Nové způsoby léčby začaly být používány i u chorob běžných, jakými jsou např. metabolické poruchy (diabetes), a dokonce u takových, které nás sužují stále častěji, jako nejrůznější malignity a nemoci centrální nervové soustavy (např. Alzheimerova choroba). Cílem genové terapie jsou geny, jejichž změny v podobě patogenních variant (dříve mutací) vyvolávají poruchy fenotypu. Naší snahou je buď jejich vyřazení z funkce (např. u hemoglobinopatií), nebo jejich nahrazení geny s normální funkcí. Ty lze do genomu vnést pomocí některého z vhodných přenašečů (tzv. vektorů), jakými jsou např. viry nebo lipozomy. Proces GT může probíhat přímo v těle pacienta (in vivo), nebo mimo něj na jeho izolovaných buňkách (ex vivo), kterými jsou obvykle indukované pluripotentní kmenové buňky (iPSC – induced pluripotent stem cell). Po úpravě se tyto buňky vracejí do pacientova těla, aby tak naplnily svůj „úděl“. V širším slova smyslu může být GT namířena i na produkt genové transkripce, kterým je messenger RNA (mRNA), nebo konečný produkt realizace genové funkce, jakým jsou funkční bílkoviny (např. u cystické fibrózy). U různých chorob se úspěšně používají uvedené přístupy v závislosti na jejich dostupnosti, která je mimo jiné dána i náklady s GT spojenými nebo přístupností cílové tkáně. Nejen ověřování účinnosti a bezpečnosti GT, ale i ekonomické důvody rozhodují o tom, proč se GT rozvíjí jen pozvolna a proč se jí ujímají většinou jen velké a bohaté instituce. Rozhodující je také to, že celý proces vývoje od výchozích experimentálních prací přes klinické zkoušky až ke konečnému přípravku běžně trvá i dekádu či déle.

Gene therapy is gradually becoming a mainstream treatment modality and is no longer the preserve of large university departments whose laboratories master nucleic acid analytical procedures and whose clinical teams manage its administration. It was originally designed for genetic diseases that, because of their prevalence, were a group known as rare diseases. Gene therapy has so far been applied in children to act before the disease development. These new treatments have also begun to be applied for common diseases such as metabolic disorders (e. g. diabetes) and even for those that are increasingly affecting us, such as various malignancies and diseases of the central nervous system (e. g. Alzheimer’s disease). The targets targeted by GT are genes, where pathogenic alterations in the form of pathogenic variants (formerly mutations) induce phenotypic disorders, and our aim is either to knock them out of function (e. g. haemoglobinopathies) or to replace them with genes with normal function, which we introduce into the genome using one of the appropriate vectors, such as viruses or liposomes. The process of GT can take place directly inside the patient's body (in vivo) or outside the body on isolated cells (ex vivo), which are usually stem cells (iPSCs, induced pluripotent stem cell). After treatment, these cells are returned to the patient's body to fulfil their "destiny". In a broader sense, GT can target the product of gene transcription, which is the messenger RNA, or the end product of gene function, such as functional proteins (eg. cystic fibrosis). Any of these approaches have been used successfully in various diseases, depending on their availability, which is determined, among other things, by the costs associated with GT or the accessibility of the target tissue. Ultimately, it is not only the validation of the efficacy and safety of GT, but also economic reasons that determine why GT has been slow to develop and is mostly undertaken only by large and wealthy institutions. Another decisive factor is that from initial experimental work through clinical trials, the whole process of its development normally takes up to a decade.

• MeSH
• cystická fibróza genetika   terapie   MeSH
• deficit alfa1-antitrypsinu genetika   terapie   MeSH
• Duchennova muskulární dystrofie genetika   terapie   MeSH
• genetická terapie * metody   MeSH
• Huntingtonova nemoc genetika   terapie   MeSH
• krevní nemoci genetika   terapie   MeSH
• lidé MeSH
• myotonická dystrofie genetika   terapie   MeSH
• nádory genetika   terapie   MeSH
• retinopathia pigmentosa genetika   terapie   MeSH
• spinální svalová atrofie genetika   terapie   MeSH
• vzácné nemoci * genetika   terapie   MeSH
• Check Tag
• lidé MeSH

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

• MeSH
• cystická fibróza * terapie   MeSH
• kvalita života MeSH
• lidé MeSH
• standardní péče MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Publikace se zaměřila na vzácné nemoci a vzácné genetické nemoci, které se vyskytují v romské populaci. Určeno odborné veřejnosti.

• MeSH
• genetické nemoci vrozené etnologie   MeSH
• Romové MeSH
• vzácné nemoci etnologie   genetika   MeSH
• Geografické názvy
• Česká republika MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• vzácné nemoci
• genetika, lékařská genetika
• NLK Publikační typ
• kolektivní monografie

BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

• MeSH
• časové faktory MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genetické testování metody   MeSH
• genotyp * MeSH
• hypertrofická kardiomyopatie * genetika   mortalita   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• náhlá srdeční smrt etiologie   epidemiologie   MeSH
• prognóza MeSH
• progrese nemoci MeSH
• rizikové faktory MeSH
• senioři MeSH
• srdeční selhání genetika   mortalita   MeSH
• transplantace srdce MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm). METHODS: CFTR genotyping and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity. RESULTS: Altogether 18 CF-causing mutations were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births. CONCLUSION: The most commonCF-causing mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

• MeSH
• alely MeSH
• cystická fibróza * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• genetické asociační studie metody   MeSH
• genotyp MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace * MeSH
• novorozenec MeSH
• novorozenecký screening MeSH
• předškolní dítě MeSH
• protein CFTR * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Bahrajn MeSH

Cluster analyzes of facial models of autistic patients aim to clarify whether it is possible to diagnose autism on the basis of facial features and further to stratify the autism spectrum disorder. We performed a cluster analysis of sets of 3D scans of ASD patients (116) and controls (157) using Euclidean and geodesic distances in order to recapitulate the published results on the Czech population. In the presented work, we show that the major factor determining the clustering structure and consequently also the correlation of resulting clusters with autism severity degree is body mass index corrected for age (BMIFA). After removing the BMIFA effect from the data in two independent ways, both the cluster structure and autism severity correlations disappeared. Despite the fact that the influence of body mass index (BMI) on facial dimensions was studied many times, this is the first time to our knowledge when BMI was incorporated into the faces clustering study and it thereby casts doubt on previous results. We also performed correlation analysis which showed that the only correction used in the existing clustering studies-dividing the facial distance by the average value within the face-is not eliminating correlation between facial distances and BMIFA within the facial cohort.

• MeSH
• dítě MeSH
• index tělesné hmotnosti * MeSH
• lidé MeSH
• mladiství MeSH
• obličej * diagnostické zobrazování   MeSH
• poruchy autistického spektra * diagnostické zobrazování   MeSH
• předškolní dítě MeSH
• shluková analýza MeSH
• zobrazování trojrozměrné * metody   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• cystická fibróza * MeSH
• individualizovaná medicína MeSH
• kolforsin farmakologie   MeSH
• lidé MeSH
• mutace MeSH
• protein CFTR genetika   MeSH
• střevní sliznice MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

PURPOSE: Crohn's disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H2O2 in the bowel. Reduced H2O2 levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described. METHODS: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn's disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied. RESULTS: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T; p.R1216W and a maternally inherited variant c.3391G>A; p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H2O2 generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease. CONCLUSIONS: Identifying novel variants in patients with Crohn's disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely "monogenic" rare forms of inflammatory bowel disease.

• MeSH
• Crohnova nemoc * genetika   MeSH
• duální oxidázy genetika   MeSH
• idiopatické střevní záněty * genetika   MeSH
• lidé MeSH
• mladiství MeSH
• peroxid vodíku MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH