Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

• MeSH
• checkpoint kinasa 2 * genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * genetika   MeSH
• introny * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * genetika   MeSH
• nádory vaječníků genetika   MeSH
• prekurzory RNA genetika   MeSH
• sestřih RNA * genetika   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Německo MeSH

BACKGROUND: A subcutaneous formulation of infliximab (IFX-SC) approved to treat patients with inflammatory bowel disease may offer improved efficacy versus intravenous infliximab. METHODS: Patients with refractory Crohn's disease (CD, n = 32) previously treated unsuccessfully with at least 2 biologics were treated with IFX-SC and followed from baseline at Week 0 (W0) to Week 30 (W30). The study's primary endpoint was the treatment's persistence at W30, while secondary goals included the analysis of serum infliximab trough levels (TL IFX), dynamics of anti-IFX antibodies (ATIs), and clinical, serum and fecal markers of CD activity during IFX-SC treatment. RESULTS: Midterm treatment persistence with the continuation of treatment after W30 was 53%. TL IFX median values showed rapid, significant upward dynamics and exceeded 15.5 μg/mL at W30, whereas median ATI levels significantly declined. Among ATI-negative patients at W0 (n = 15), only one showed IFX immunogenicity with newly developed ATIs at W30. Among ATI-positive patients at W0, ATI seroconversion from ATI-positive to ATI-negative status was observed in 10 of 17 patients (58.8%). Patients who had continued IFX-SC treatment at W30 showed significant decreases in C-reactive protein (P = .0341), fecal calprotectin (P = .0002), and Harvey-Bradshaw index (P = .0029) since W0. CONCLUSIONS: Patients with refractory CD previously treated with at least 2 biologics exhibited clinically relevant improvement with IFX-SC, which showed less immunogenic potential than IFX-IV and highly stable TL IFX.

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Knowledge on the immunogenicity of anti-SARS-CoV-2 vaccines in inflammatory bowel disease [IBD] patients is limited. Therefore, SARS-CoV-2-specific T-cell responses and antibodies were analysed in 60 IBD vaccine recipients and 30 controls. METHODS: SARS-CoV-2 IgG antibodies against the viral spike protein were measured at baseline and at 8 and 26 weeks after the second vaccine dose. SARS-CoV-2 IgG antibodies against the nucleocapsid antigens were measured at week 26. A SARS-CoV-2 interferon-gamma released assay [IGRA] was performed in all vaccinees at week 26. RESULTS: At weeks 0 and 8, no differences were found in anti-spike antibodies between cohorts. At week 26, the decrease in antibody levels was more significant in the IBD cohort compared to the healthy cohort, and anti-nucleocapsid antibodies were not detected in either group. At week 26, 16 of 90 [18%] vaccinated individuals had a negative IGRA test result, seven of 90 [8%] were borderline and 67 [74%] had a positive IGRA result; 22 of the 23 individuals with negative or borderline IGRA results belonged to the IBD cohort. However, the overall functional ability of T-lymphocytes to produce interferon-gamma after the unspecific mitogen stimulation was lower in IBD patients. In vaccinated individuals with low or borderline IGRA, treatment with tumour necrosis factor-alpha inhibitors was the most frequent. In individuals with a significant drop in anti-spike antibody levels, plasmatic interferon-gamma concentrations after the specific SARS-CoV-2 stimulation were also insufficient. CONCLUSIONS: Simple humoral and cellular post-vaccination monitoring is advisable in IBD patients so that repeated vaccine doses may be scheduled.

• MeSH
• COVID-19 * prevence a kontrola   MeSH
• humorální imunita MeSH
• idiopatické střevní záněty * farmakoterapie   MeSH
• imunoglobulin G MeSH
• interferon gama MeSH
• lidé MeSH
• protilátky virové MeSH
• SARS-CoV-2 MeSH
• vakcinace MeSH
• vakcíny proti COVID-19 MeSH
• virové vakcíny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Patients with inflammatory bowel disease (IBD) on immune-modifying treatment could be at an increased risk for severe coronavirus disease 2019 (COVID-19); thus, data on the efficacy and safety of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted a prospective study of IBD patients vaccinated with BNT162b2, CX-024414, and ChAdOx1 nCoV-19 vaccines. The aim was to evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD. METHODS: The study included 602 IBD patients and 168 immunocompetent health care workers serving as controls. Serum anti-SARS-CoV-2 IgG antibodies were measured by chemiluminescent microparticle immunoassay before the vaccination and 8 weeks after the vaccination. RESULTS: Of IBD patients, 82.2% were receiving biological treatment: most of them were treated with antitumor necrosis factor (TNF)-α inhibitors (48.5%), and just under half of them were treated with concomitant thiopurines or methotrexate, followed by vedolizumab (18.6%) and ustekinumab (15.1%). Only 8.1% of patients were on 5-aminosalicylates, and a minority (2.2%) were treatment-free. The postvaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%. Median anti-SARS-CoV-2 IgG levels were lower among IBD recipients of ChAdOx1 nCoV-19 compared with 2 other vaccines (P < .0001) and control ChAdOx1 nCoV-19 recipients (P = .01). No correlation was found between serum trough levels and anti-SARS-CoV-2 IgG concentrations for any of the biological drugs used. The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response (P < .0001). When evaluating the laboratory activity of IBD by C-reactive protein and fecal calprotectin levels, no significant differences were found before the vaccination and 8 weeks after its completion. CONCLUSIONS: Our findings warrant particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators and show the priority of mRNA vaccines in this specific group of patients.

• MeSH
• C-reaktivní protein metabolismus   MeSH
• ChAdOx1 nCoV-19 MeSH
• COVID-19 * prevence a kontrola   MeSH
• idiopatické střevní záněty * farmakoterapie   MeSH
• imunoglobulin G MeSH
• leukocytární L1-antigenní komplex MeSH
• lidé MeSH
• methotrexát MeSH
• prospektivní studie MeSH
• protilátky virové MeSH
• SARS-CoV-2 MeSH
• TNF-alfa metabolismus   MeSH
• tvorba protilátek MeSH
• ustekinumab MeSH
• vakcína BNT162 MeSH
• vakcinace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Hearing loss (HL) is the most common sensory deficit in humans. HL is an extremely heterogeneous condition presenting most frequently as a nonsyndromic (NS) condition inherited in an autosomal recessive (AR) pattern, termed DFNB. Mutations affecting the STRC gene cause DFNB type 16. Various types of mutations within the STRC gene have been reported from the U.S. and German populations, but no information about the relative contribution of STRC mutations to NSHL-AR among Czech patients is available. METHODS AND PATIENTS: Two hundred and eighty-eight patients with prelingual NSHL, either sporadic (n = 207) or AR (n = 81), who had been previously tested negative for the mutations affecting the GJB2 gene, were included in the study. These patients were tested for STRC mutations by a quantitative comparative fluorescent polymerase chain reaction (QF-PCR) assay. In addition, 31 of the 81 NSHL-AR patients were analyzed by massively parallel sequencing using one of two different gene panels: 23 patients were analyzed by multiplex-ligation probe amplification (MLPA); and 9 patients by SNP microarrays. RESULTS: Causal mutations affecting the STRC gene (including copy number variations [CNVs] and point mutations) were found in 5.5% of all patients and 13.6% of the 81 patients in the subgroup with NSHL-AR. CONCLUSION: Our results provide strong evidence that STRC gene mutations are an important cause of NSHL-AR in Czech HL patients and are probably the second most common cause of DFNB. Large CNVs were more frequent than point mutations and it is reasonable to test them first by a QF-PCR method-a simple, accessible, and efficient tool for STRC CNV detection, which can be combined by MLPA.

• MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace * MeSH
• nedoslýchavost genetika   MeSH
• polymerázová řetězová reakce MeSH
• sekvenční delece MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.

• MeSH
• chromozomální delece MeSH
• dítě MeSH
• ekzém etiologie   MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• fibromatóza dásní genetika   MeSH
• hypertrichóza genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 17 * genetika   MeSH
• mentální retardace etiologie   MeSH
• mikrocefalie etiologie   MeSH
• obličej abnormality   MeSH
• poruchy růstu etiologie   MeSH
• telomery * MeSH
• vývojové poruchy u dětí etiologie   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

OBJECTIVE: To highlight importance of detailed ultrasound examination in fetuses with known normal karyotype (and micro-array result) from CVS. In case of markedly abnormal ultrasound result repeated karyotyping by amniocentesis should be considered. Sample should be analyzed by routine cytogenetic techniques, however also micro-array and targeted FISH should be added in order to achieve most accurate diagnosis. CASE REPORT: We report prenatal diagnosis of Pallister-Killian Syndrome (PKS) at 18 gestational weeks. The mother asked us for second opinion scan in our centre due to finding of seven soft markers of chromosomal defects in fetus with normal CVS result. Our examination revealed asymmetrical fetal growth, normohydramnion, spastic fetal movements and several abnormalities: nuchal edema, mild bilateral hydronephrosis, omphalocoele and facial anomalies. We asked for targeted genetic analysis for PKS. Amniocentesis with repeated genetic analysis confirmed PKS (80% mosaicism of tetrasomy 12p). CONCLUSION: Diagnosis of PKS led mother to terminate pregnancy.

• MeSH
• amniocentéza MeSH
• chromozomální poruchy diagnóza   embryologie   genetika   MeSH
• dospělí MeSH
• druhý trimestr těhotenství MeSH
• genetické testování metody   MeSH
• gestační stáří MeSH
• lidé MeSH
• lidské chromozomy, pár 12 genetika   MeSH
• mozaicismus MeSH
• odběr choriových klků * MeSH
• prenatální diagnóza metody   MeSH
• těhotenství MeSH
• ultrasonografie prenatální * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• kmenové buňky metabolismus   patologie   MeSH
• lidé MeSH
• limbus corneae metabolismus   patologie   MeSH
• nemoci rohovky genetika   metabolismus   patologie   MeSH
• rohovkový epitel metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning "bins" yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27- CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes' immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ CD4+ T-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.

• MeSH
• aktivace lymfocytů MeSH
• B-lymfocyty imunologie   MeSH
• běžná variabilní imunodeficience imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• fibróza MeSH
• idiopatická trombocytopenická purpura imunologie   MeSH
• imunosenescence MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• plíce patologie   MeSH
• průtoková cytometrie MeSH
• senioři MeSH
• separace buněk MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype. METHODS: DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings. RESULTS: All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer. CONCLUSIONS: The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.

• MeSH
• dědičné nemoci očí diagnóza   genetika   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• elektroretinografie MeSH
• fenotyp MeSH
• genotyp MeSH
• homozygot MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• oční proteiny genetika   metabolismus   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• retina diagnostické zobrazování   metabolismus   patofyziologie   MeSH
• retinální dystrofie diagnóza   genetika   metabolismus   MeSH
• rodokmen MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH