• MeSH
• dilatační kardiomyopatie genetika   MeSH
• genetické testování metody   MeSH
• hypertrofická kardiomyopatie genetika   MeSH
• lidé MeSH
• restriktivní kardiomyopatie genetika   MeSH
• sekvenování exomu metody   MeSH
• srdeční selhání * genetika   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Ačkoliv se jednotlivé typy malformací kortikálního vývoje (MCD) vyskytují relativně vzácně, pacienti s různými typy MCD tvoří významnou část neurologicky nemocných. Genetické vyšetření, ať už DNA získané z krve anebo z dysplastické mozkové tkáně, může přinést objasnění genetické příčiny onemocnění pacienta, a tím ovlivnit jak postup léčby a sledování samotného pacienta, tak další reprodukční rozhodnutí rodiny. Nezbytnou podmínkou úspěchu genetického vyšetřování je kvalitní a přesný popis fenotypu pacienta - zejména nálezu na MRI. Délka samotného vyšetření trvá řádově měsíce, ale v případě nálezu varianty v genu doposud nespojovaném s MCD se může protáhnout i na roky. Znalosti genetických příčin vzniku MCD mohou v budoucnu vést k lepšímu pochopení jejich patogeneze a k vývoji nových cílených léčiv, případně i genové terapie.

Although respective types of malformations of cortical development (MCD) are rare, patients with all MCD constitute a significant proportion of neurology in- and outpatient clinics. Genetic testing of blood- or brain tissue-derived DNA can elucidate genetic causes of MCD and thereby influence future patient management and reproductive choices of patients and their families. High-quality MRI and detailed phenotype description constitute the cornerstone of MCD diagnostic process. Genetic testing and analysis may take months, and functional studies of variants in novel genes, previously not associated with MCD may last even longer.

• MeSH
• fokální kortikální dysplazie MeSH
• genetické testování metody   MeSH
• lidé MeSH
• malformace mozkové kůry * genetika   MeSH
• sekvenování exomu metody   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

• MeSH
• genetická predispozice k nemoci MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   MeSH
• invazivní růst nádoru genetika   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• onkogeny MeSH
• pohyb buněk genetika   MeSH
• proliferace buněk genetika   MeSH
• protein vázající element responzivní pro cyklický AMP genetika   MeSH
• protoonkogenní proteiny c-akt genetika   MeSH
• rodina MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• senioři MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

• MeSH
• alfa karyoferiny genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• spastická paraplegie dědičná genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

• MeSH
• centra terciární péče MeSH
• dítě MeSH
• dospělí MeSH
• exom genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetická variace genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurovývojové poruchy genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• sekvenování exomu metody   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Aims: Genomic studies play a major role in variant observations between and within populations and in identifying causal relationships between genotypes and phenotypes. Analyses using databases such as gnomAD can provide insight into the frequencies of alleles in large populations. There have been reports that detail such frequencies for several countries and ethnic groups, but as yet, there are no such datasets for the Czech population. Patients and Methods: Whole-exome sequencing (WES) data from 222 individuals from the Czech Republic were analyzed by The Genome Analysis Toolkit best practices pipeline. These data were annotated with the ANNOVAR tool, and the allele frequencies were computed. Results: We developed a database that contains 300,111 variants in 17,512 genes. It is accessible through a simple web query available at prot2hg.com/variantbrowser. Gene-based analyses identified those genes that are most tolerant to variants in our population. Second, allele frequencies in our population were compared to the gnomAD database and groups of variants frequent in our population, but ultra-rare in gnomAD as a whole were identified. Conclusion: This tool should be useful for detecting local variants in the Czech population of patients with neurogenetic diseases.

• MeSH
• alely MeSH
• databáze genetické * MeSH
• dospělí MeSH
• fenotyp MeSH
• frekvence genu genetika   MeSH
• genetická variace genetika   MeSH
• genomika metody   MeSH
• genotyp MeSH
• lidé MeSH
• nemoci nervového systému genetika   MeSH
• neurodegenerativní nemoci genetika   MeSH
• sekvenční analýza DNA metody   MeSH
• sekvenování exomu metody   MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• dataset MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

• MeSH
• dítě MeSH
• dystonie diagnóza   epidemiologie   genetika   MeSH
• exom genetika   MeSH
• genetická variace genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Východiska: Nádorová onemocnění jsou ve většině případů multifaktoriální etiologie, na jejich vzniku se podílejí jak faktory vnějšího, tak vnitřního prostředí. Hereditární nádorové syndromy jsou převážně autozomálně dominantně dědičná onemocnění, s neúplnou, nicméně velmi vysokou penetrancí. Případ: Osmnáctiletá pacientka, virgo, přichází v červnu 2018 k ošetřujícímu gynekologovi pro metroragii. Magnetická rezonance pánve odhalí tumor velikosti 80 x 90 x 80 mm vycházející z oblasti děložního hrdla. Histologicky je potvrzen velmi vzácný, tzv. hyperkalcemický typ malobuněčného karcinomu děložního hrdla. Došetření germinálního exomu odhalilo patogenní variantu genů PALB2 a BRCA2 s doporučením podrobného vyšetření cestou lékařské genetiky. Závěr: Klinické zkušenosti s tímto typem nádoru jsou velmi omezené, ale nacházejí průnik v několika aspektech - gynekologické malobuněčné karcinomy jsou velice vzácná agresivní onemocnění s velmi špatnou prognózou, postihující převážně mladé ženy. Nejčastěji vycházejí z vaječníků, na tato onemocnění je relativně nejvíce dat, ale jsou popsány i případy lokalizace na cervixu, endometriu, v pochvě i vulvě. Jedná se o extrémně vzácný případ nádorového onemocnění, což dokumentuje i nedostatek klinických dat a popsaných kazuistik z celého světa, v našem případě spojeného s velmi málo pravděpodobnou genetickou mutační náloží, kterou pacientka získala od svých rodičů. Vzhledem k této zkušenosti doporučujeme při podobném nálezu pečlivě odebrat rodinou anamnézu a zvážit genetické testování.

Background: Oncological diseases have, in most cases, a multifactorial etiology, composed of a combination of external and internal environmental factors. Hereditary tumorous syndromes are mostly autosomal dominant diseases with incomplete but very high penetrance. Observation: The patient, an 18-year-old virgin female, consulted a gynecologist in June 2018 because of metrorrhagia. Magnetic resonance imaging revealed a cervical tumor with the dimensions 80 x 90 x 80 mm. Histological analysis confirmed the presence of a very rare hypercalcemic type of small-cell carcinoma of the cervix. Further investigation of the germinal exom of the patient showed pathological variations in genes PALB2 and BRCA2, presented with recommendation of detailed examination by medical genetics. Conclusion: Clinical experience with this type of tumor is very limited, but it still comes with some useful outcome. Small cell carcinomas of the gynecologic tract are very rare, aggressive diseases, with very poor prognosis, affecting mainly young women. Their origin is most often the ovaries, based on most clinical data, but these tumor also localize to the endometrium, cervix, vagina and vulva. It is an extremely rare type of cancer, for which clinical data is scant due to the extremely low number of reported cases. In this patient, the carcinoma had an unusual genetical mutation burden, which she inherited from her parents. In the light of these findings, we recommend that patients suspected of having a small-cell of the gynecologic tract provide a detailed family history, and that genetic testing be considered in similar cases.

• MeSH
• dědičné nádorové syndromy diagnóza   genetika   terapie   MeSH
• geny BRCA2 MeSH
• laparotomie metody   MeSH
• lidé MeSH
• malobuněčný karcinom diagnóza   genetika   terapie   MeSH
• mladiství MeSH
• mutace MeSH
• nádory děložního čípku * diagnóza   genetika   terapie   MeSH
• protein FANCN MeSH
• protokoly protinádorové léčby MeSH
• radioterapie metody   MeSH
• sekvenování exomu metody   MeSH
• smrt MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. CASE PRESENTATION: A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. CONCLUSIONS: Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

• MeSH
• fatální výsledek MeSH
• Heřmanského-Pudlákův syndrom * diagnóza   genetika   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace MeSH
• plíce diagnostické zobrazování   patologie   MeSH
• plicní fibróza * diagnóza   genetika   patofyziologie   MeSH
• počítačová rentgenová tomografie metody   MeSH
• progrese nemoci MeSH
• sekvenování exomu metody   MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

CONTEXT: Familial short stature (FSS) is a term describing a growth disorder that is vertically transmitted. Milder forms may result from the combined effect of multiple genes; more severe short stature is suggestive of a monogenic condition. The etiology of most FSS cases has not been thoroughly elucidated to date. OBJECTIVES: To identify the genetic etiology of severe FSS in children treated with GH because of the diagnosis of small for gestational age or GH deficiency (SGA/GHD). DESIGN, SETTINGS, AND PATIENTS: Of 736 children treated with GH because of GHD/SGA, 33 with severe FSS (life-minimum height -2.5 SD or less in both the patient and shorter parent) were included in the study. The genetic etiology was known in 5 of 33 children prior to the study [ACAN (in 2], NF1, PTPN11, and SOS1). In the remaining 28 of 33, whole-exome sequencing was performed. The results were evaluated using American College of Medical Genetics and Genomics standards and guidelines. RESULTS: In 30 of 33 children (90%), we found at least one variant with potential clinical significance in genes known to affect growth. A genetic cause was elucidated in 17 of 33 (52%). Of these children, variants in growth plate-related genes were found in 9 of 17 [COL2A1, COL11A1, and ACAN (all in 2), FLNB, FGFR3, and IGF1R], and IGF-associated proteins were affected in 2 of 17 (IGFALS and HMGA2). In the remaining 6 of 17, the discovered genetic mechanisms were miscellaneous (TRHR, MBTPS2, GHSR, NF1, PTPN11, and SOS1). CONCLUSIONS: Single-gene variants are frequent among families with severe FSS, with variants affecting the growth plate being the most prevalent.

• MeSH
• dítě MeSH
• genetická predispozice k nemoci epidemiologie   MeSH
• genetická variace * MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• lidský růstový hormon terapeutické užití   MeSH
• metaloendopeptidasy genetika   MeSH
• mladiství MeSH
• poruchy růstu farmakoterapie   epidemiologie   genetika   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• prospektivní studie MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   MeSH
• receptor IGF typ 1 genetika   MeSH
• rodokmen MeSH
• růstová ploténka účinky léků   MeSH
• sekvenování exomu metody   MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie 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
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH