Gene sequence variant
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A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- kolorektální nádory * genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- oprava DNA genetika MeSH
- rodokmen MeSH
- sekvenování exomu * metody MeSH
- senioři MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Sinonasal adenosquamous carcinoma (ASC) is a rare tumour classified as a variant of squamous cell carcinoma, exhibiting both squamous and glandular differentiation. ASC has a poorer prognosis compared to sinonasal mucoepidermoid carcinoma (MEC), another uncommon tumour in this region. ASC is believed to originate from metaplastic squamous epithelium, though it may also arise from respiratory epithelium in respiratory epithelial adenomatoid hamartoma (REAH) or seromucinous glands in seromucinous hamartoma (SH). METHODS AND RESULTS: Five cases of sinonasal ASC were retrieved from our registry. Initially, they were classified as sinonasal MEC (n = 3), ASC (n = 2), and carcinoma ex REAH (n = 1). All cases showed adenosquamous malignant proliferation beneath the surface respiratory epithelium with occasional squamous metaplasia, except for one case that showed dysplasia. The respiratory epithelium exhibited an inverted growth pattern consistent with REAH/SH, and displayed atypical sinonasal glands (ASGSH) arising within seromucinous hamartoma. Next-generation sequencing (NGS) revealed multiple pathogenic mutations in two cases, and in case 4 GGA2::PRKCB and EYA2::SERINC3 gene fusions. One case was positive for high-risk HPV. None of the cases exhibited CRTC1/3::MAML2 gene fusion. CONCLUSION: The connection between ASGSH and ASC has not been described in the literature. There is a growing need for additional studies on the morphological, immunohistochemical, and genetic aspects of these tumours. SH/REAH may serve as precursor lesions in the progression of atypical sinonasal glands to malignancy, and their role in tumour development deserves further investigation.
- MeSH
- adenoskvamózní karcinom * patologie genetika MeSH
- dospělí MeSH
- hamartom * patologie genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory vedlejších dutin nosních patologie genetika MeSH
- respirační sliznice patologie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
- MeSH
- algoritmy MeSH
- dítě MeSH
- genetické testování * metody MeSH
- lidé MeSH
- mladiství MeSH
- mutace genetika MeSH
- nanismus genetika diagnóza MeSH
- pokrevní příbuzenství * MeSH
- poruchy růstu genetika diagnóza MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- sekvenování exomu metody MeSH
- tělesná výška genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Irák MeSH
Around 180 genes have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in mice, and represent promising novel candidate genes for human CAKUT. In whole-exome sequencing data of two siblings with genetically unresolved multicystic dysplastic kidneys (MCDK), prioritizing variants in murine CAKUT-associated genes yielded a rare variant in the teashirt zinc finger homeobox 3 (TSHZ3) gene. Therefore, the role of TSHZ3 in human CAKUT was assessed. Twelve CAKUT patients from 9/301 (3%) families carried five different rare heterozygous TSHZ3 missense variants predicted to be deleterious. CAKUT patients with versus without TSHZ3 variants were more likely to present with hydronephrosis, hydroureter, ureteropelvic junction obstruction, MCDK, and with genital anomalies, developmental delay, overlapping with the previously described phenotypes in Tshz3-mutant mice and patients with heterozygous 19q12-q13.11 deletions encompassing the TSHZ3 locus. Comparable with Tshz3-mutant mice, the smooth muscle layer was disorganized in the renal pelvis and thinner in the proximal ureter of the nephrectomy specimen of a TSHZ3 variant carrier compared to controls. TSHZ3 was expressed in the human fetal kidney, and strongly at embryonic day 11.5-14.5 in mesenchymal compartments of the murine ureter, kidney, and bladder. TSHZ3 variants in a 5' region were more frequent in CAKUT patients than in gnomAD samples (p < 0.001). Mutant TSHZ3 harboring N-terminal variants showed significantly altered SOX9 and/or myocardin binding, possibly adversely affecting smooth muscle differentiation. Our results provide evidence that heterozygous TSHZ3 variants are associated with human CAKUT, particularly MCDK, hydronephrosis, and hydroureter, and, inconsistently, with specific extrarenal features, including genital anomalies.
- MeSH
- dítě MeSH
- heterozygot * MeSH
- homeodoménové proteiny genetika MeSH
- kojenec MeSH
- ledviny abnormality metabolismus MeSH
- lidé MeSH
- missense mutace MeSH
- močové ústrojí abnormality metabolismus MeSH
- multicystické dysplastické ledviny genetika MeSH
- myši MeSH
- předškolní dítě MeSH
- transkripční faktory genetika MeSH
- urogenitální abnormality genetika patologie MeSH
- vezikoureterální reflux MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Předkládáme případ 5,5letého chlapce s těžkým globálním vývojovým opožděním, hypotonií, malým proporcionálním vzrůstem, neprospíváním, kraniofaciální dysmorfií a dalšími potížemi, u kterého se podařilo stanovit diagnózu pomocí celogenomového sekvenování (WGs). diagnostika byla realizována v rámci českého národního projektu BabyFox, který se zaměřuje na zhodnocení diagnostické a klinické využitelnosti rapidního celogenomového sekvenování (rapid trioWGs) u dětí hospitalizovaných na jednotkách intenzivní péče s podezřením na genetickou podstatu jejich potíží. u pacienta byla identifikována patogenní varianta v genu RNU4-2, která je od roku 2024 spojována s prevalentním onemocněním rnu4-2 syndromem neurovývojového opoždění, také známým pod názvem renu syndrom. ačkoli se jedná o nově popsané onemocnění, je renu syndrom jedním z nejrozšířenějších monogenních neurovývojových onemocnění, přičemž se odhaduje, že patogenní varianty v genu RNU4-2 jsou příčinou přibližně 0,4 % všech neurovývojových poruch. tento gen nekóduje protein, ale malou jadernou rna u4, díky čemuž jeho sekvence není stanovována při standardním celoexomovém sekvenování ani v rámci cílených sekvenačních panelů. Jeho význam tak zůstával až do roku 2024 přehlížen. případ renu syndromu zdůrazňuje význam celogenomového sekvenování pokrývajícího i nekódující části genomu v diagnostice vzácných genetických onemocnění a ukazuje, jak implementace moderních genomických metod může přispět k ukončení diagnostické odysey pacientů s dosud neobjasněnými neurovývojovými poruchami.
We present the case of a 5 and half year-old boy with severe global developmental delay, hypotonia, severe growth failure, failure to thrive, craniofacial dysmorphism, and other difficulties, who was diagnosed by whole genome sequencing (WGs). the diagnosis was carried out within the czech national project BabyFox. a pathogenic variant in the RNU4-2 gene was identified in the patient, which has been associated with the prevalent disorder known as rnu4-2 neurodevelopmental delay syndrome, also known as renu syndrome since 2024. although it is a newly described diseases, renu syndrome is one of the most prevalent monogenic neurodevelopmental disorder, with pathogenic variants in the rnu4-2 gene estimated to cause approximately 0.4% of all neurodevelopmental disorders. this gene does not encode a protein but rather a small nuclear rna u4, which means its sequence is not captured by standard whole-exome sequencing or targeted sequencing panels. as a result, its significance remained overlooked until 2024. the case of renu syndrome highlights the importance of whole-genome sequencing, which covers non-coding regions of the genome, in the diagnosis of rare genetic disorders. it also demonstrates how the implementation of modern genomic methods can help end the diagnostic odyssey for patients with previously unexplained neurodevelopmental disorders.
- Klíčová slova
- gen RNU4-2, ReNU syndrom,
- MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- mikrocefalie diagnóza etiologie genetika MeSH
- neprospívání diagnóza etiologie MeSH
- neurovývojové poruchy * diagnóza genetika klasifikace MeSH
- předškolní dítě MeSH
- RNA malá jaderná genetika MeSH
- sekvenování celého genomu metody MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- kazuistiky MeSH
The purpose of this study is to elucidate the genetic causes and phenotypic presentation of nonfamilial tall stature (nFTS) and to compare these findings with those of familial tall stature (FTS) from the same population that was previously studied. Children with nFTS (defined as a height > + 2 SDs with both parents' heights < + 2 SDs) underwent endocrine and anthropometric examinations and genetic testing (karyotyping, SHOX gene dosage analysis and next-generation sequencing of 786 growth-associated genes). Exome sequencing was performed in patients with negative genetic results and a height > + 3 SDs. A total of 55 children with nFTS were enrolled. The median height was + 2.8 SD (2.4-3.2 SD), and the median midparental height was + 0.7 SD (0.4-0.9 SD). Genetic causes of tall stature were identified in 6/55 (11%) children. Specifically, four children had gonosomal aneuploidy (47,XXY [2x], 47,XXX, 48,XXXX), one had a heterozygous complex rearrangement including SHOX gene duplication, and one carried a pathogenic variant in the TGFBR2 gene leading to Loeys-Dietz syndrome. A genetic cause of tall stature was significantly less common in nFTS (11%) than in our previously published cohort with FTS (32%). Conclusion: Cytogenetic abnormalities were the predominant genetic alteration identified in children with nFTS, confirming the justification of karyotype analysis in this cohort. The probability of genetic alterations was greater in children with FTS than in those with nFTS. Our findings suggest that the current guidelines for complex investigation are efficient for children with nFTS but need revision in children with FTS. What is known - what is new • Although tall stature is generally considered beneficial, it can be associated with health risks which need to be recognized in time. Tall stature without intellectual impairment is usually considered to be polygenic. • However, the cause of familial tall stature was monogenic more often than it was thought previously. • Children with non-familial and apparently non-syndromic tall stature have never been systematically investigated. • Monogenic causes of non-familial tall stature were observed in 11% of patients, including a participant with Loeys-Dietz syndrome.
- MeSH
- chromozomální aberace * MeSH
- dítě MeSH
- fenotyp MeSH
- genetické testování MeSH
- karyotypizace MeSH
- lidé MeSH
- mladiství MeSH
- poruchy růstu * genetika MeSH
- předškolní dítě MeSH
- protein SHOX MeSH
- sekvenování exomu MeSH
- tělesná výška * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
BACKGROUND: Since the incidence of vancomycin-resistant enterococci (VRE) is increasing and treatment options remain limited, we aimed to investigate the epidemiology of vancomycin- and tigecycline-resistant enterococci in a university hospital using whole genome sequencing (WGS). METHODS: Between April and December 2021, 102 VRE isolates were collected from a single tertiary care hospital in the Czech Republic. Forty selected isolates underwent antimicrobial susceptibility testing and WGS (Illumina short reads and long reads with MinION in selected isolates). RESULTS: All Enterococcus faecium isolates were resistant to ampicillin, carrying the PBP5_Met485Ala, PBP5_Glu629Val, and fluoroquinolones carrying the GyrA_Ser83Ile and ParC_Ser80Ile substitutions. The vanA operon was found on pELF2-like plasmids and plasmids carrying rep17 and/or rep18b genes. The novel Tn1546 structural variants were identified in vanA-carrying isolates. The vanB operon was located on the chromosome within a Tn1549 structural variant. Linezolid resistance was detected in one isolate carrying the 23S rDNA_G2576T substitution. Twenty-two isolates were resistant to tigecycline (tet(L), tet(M) and rpsJ_del 155-166 or RpsJ_Lys57Arg). Discrepancies between phenotypic and genotypic resistance profiles were observed for daptomycin (RpoB_Ser491Phe), trimethoprim/sulfamethoxazole (dfrG gene), nitrofurantoin (NmrA_Gln48Lys substitution without the EF0404 and EF0648 genes) and tetracycline (truncated TetM). The two multilocus sequence typing (MLST) schemes identified different numbers of STs: 5 STs, with ST117 as the predominant one (n = 32, 80%), versus 10 STs, with ST138 (27.5%), ST136 (25%), and ST1067 (20%) being the most frequent, respectively. The whole genome MLST revealed clonal clustering (0-7 allele differences) among isolates of the same ST. When comparing ST117 isolates from our study with 2,204 ST117 isolates from 15 countries, only one Czech isolate clustered closely with strains from Germany and the Netherlands, differing by just 16 alleles. CONCLUSIONS: The spread of E. faecium isolates ST117 resistant to vancomycin and tigecycline was identified. The discrepancies between resistance genotypes and phenotypes highlight the importance of combining molecular and phenotypic surveillance in antimicrobial resistance monitoring.
- MeSH
- antibakteriální látky * farmakologie MeSH
- bakteriální proteiny genetika MeSH
- Enterococcus faecium * genetika účinky léků izolace a purifikace klasifikace MeSH
- enterokoky rezistentní vůči vankomycinu * genetika účinky léků izolace a purifikace MeSH
- genom bakteriální MeSH
- grampozitivní bakteriální infekce * mikrobiologie epidemiologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence genetika MeSH
- multilokusová sekvenční typizace MeSH
- rezistence na vankomycin genetika MeSH
- sekvenování celého genomu MeSH
- tigecyklin * farmakologie MeSH
- vankomycin * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Processes shaping the formation of the present-day population structure in highly urbanized Northern Europe are still poorly understood. Gaps remain in our understanding of when and how currently observable regional differences emerged and what impact city growth, migration, and disease pandemics during and after the Middle Ages had on these processes. RESULTS: We perform low-coverage sequencing of the genomes of 338 individuals spanning the eighth to the eighteenth centuries in the city of Sint-Truiden in Flanders, in the northern part of Belgium. The early/high medieval Sint-Truiden population was more heterogeneous, having received migrants from Scotland or Ireland, and displayed less genetic relatedness than observed today between individuals in present-day Flanders. We find differences in gene variants associated with high vitamin D blood levels between individuals with Gaulish or Germanic ancestry. Although we find evidence of a Yersinia pestis infection in 5 of the 58 late medieval burials, we were unable to detect a major population-scale impact of the second plague pandemic on genetic diversity or on the elevated differentiation of immunity genes. CONCLUSIONS: This study reveals that the genetic homogenization process in a medieval city population in the Low Countries was protracted for centuries. Over time, the Sint-Truiden population became more similar to the current population of the surrounding Limburg province, likely as a result of reduced long-distance migration after the high medieval period, and the continuous process of local admixture of Germanic and Gaulish ancestries which formed the genetic cline observable today in the Low Countries.
- MeSH
- dějiny středověku MeSH
- genetická variace MeSH
- genom lidský MeSH
- genomika MeSH
- lidé MeSH
- mor epidemiologie dějiny genetika MeSH
- populační genetika MeSH
- urbanizace * dějiny MeSH
- Check Tag
- dějiny středověku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- Geografické názvy
- Belgie MeSH
BACKGROUND: Diagnosing primary or secondary CNS lymphoma (CNSL) is a clinical challenge due to the limitations of standard biopsy and imaging procedures despite established guidelines. Therefore, accurate biomarkers and analytical methods that are convenient for practical routine use are needed to diagnose and manage these aggressive lymphomas effectively. We evaluated the utility of minimally invasive circulating tumor DNA (ctDNA) detection in a prospective real-world scenario, moving this approach closer to clinical practice. METHODS: A total of 164 plasma, cerebrospinal fluid (CSF), and tumor samples from 56 CNSL patients were collected to analyze tumor DNA by the diagnostic next-generation sequencing (NGS) panel LYNX, enabling simultaneous analysis of gene variants, chromosomal aberrations, and antigen receptor rearrangements in targeted regions. RESULTS: The well-known genetic heterogeneity of CNSL was refined with integrative molecular data, showing the most frequent MYD88, PIM1, and KMT2D mutations and a broad spectrum of chromosomal aberrations, reflecting high genomic complexity. The multi-target approach achieved a substantially higher detection rate of CNS infiltration (90%) than tracking a single variant in gene MYD88 (46%). CSF clearly surpasses plasma if applying a routine (non-ultrasensitive) NGS approach and allows for more reliable evidence of CNS involvement than conventional flow cytometry (91% vs. 21%, p < 0.001). Parallel analysis of tumor DNA in both cell-free and cellular DNA from CSF makes the probability of primary or secondary CNS malignancy detection even higher. CONCLUSIONS: Our prospective, tissue-agnostic approach highlights the feasibility of ctDNA sequencing by a commonplace and affordable method, offering higher sensitivity to detect CNS infiltration with lymphoma than standard cell-analyzing techniques. We accentuate the benefit of a multi-target NGS approach and adequate CSF sampling to obtain satisfactory diagnostic yield. Less invasive liquid biopsy testing by comprehensive NGS complements standard procedures in the diagnostics and management of CNSL patients, especially when encountering limitations.
- Publikační typ
- časopisecké články MeSH
The RFC4 gene has recently been linked to a multisystemic disorder Morimoto-Ryu-Malicdan neuromuscular syndrome, with myopathy being one of the key symptoms described in nine patients. We report the case of two brothers with a rapidly progressive congenital myopathy characterized by severe hypotonia and axial muscle weakness associated with previously unpublished biallelic variants in the RFC4 gene. Whole exome sequencing revealed biallelic variants NM_002916.5:c.1019_1020insCAAA and NM_002916.5:c.982_983insACT, corresponding to the protein-level changes p.(Gly341Lysfs*4) and p.(Thr328delinsAsnSer) in both brothers. This case expands the phenotypic spectrum of Morimoto-Ryu-Malicdan neuromuscular syndrome, highlighting severe early-onset axial muscle weakness, severe hypotonia, and preserved intellectual development. We also provide novel insights into the clinical progression and potential multidisciplinary interventions for patients with Morimoto-Ryu-Malicdan neuromuscular syndrome. Our findings highlight the importance of advanced genetic diagnostics and international collaboration in identifying rare neuromuscular diseases and improving the clinical management of affected patients.
- MeSH
- dítě MeSH
- fenotyp MeSH
- lidé MeSH
- myotonia congenita * genetika patofyziologie MeSH
- předškolní dítě MeSH
- progrese nemoci MeSH
- sourozenci MeSH
- svalová hypotonie * genetika patofyziologie MeSH
- svalová slabost * genetika patofyziologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH