Syndromy z mozaicizmu jsou charakterizovány: 1) Jedinec vzniklý z jediné zygoty má dvě či více linií buněk (klonů) geneticky či funkčně odlišných (chimerizmus). 2) Fenotypová variabilita nositelů je velmi rozsáhlá v závislosti na podílu zastoupení jednotlivých linií. 3) Klinická prognóza mozaik je lepší než u forem vzniklých důsledkem mutace ve všech buňkách jedince. Kompletní formy mutace jsou často prenatálně letální. 4) Genetická prognóza reprodukce příbuzných mozaik je vesměs bez zvýšeného genetického rizika, prognóza vlastní reprodukce je spojena se zvýšeným rizikem v závislosti na okamžiku vzniku mutace – před či po oddělení buněk pro budoucí gonády. 5) Diagnostický průkaz mozaiky je u mixoploidů (mozaiky chromozomálních mutací) možný mnohdy jen z buněk různých zárodečných listů (fibroblasty, lymfocyty), mozaiky genových mutací jsou často zjistitelné jen v okrscích postižené kůže. 6) Klinicky jsou signálními příznaky mozaiky asymetrie těla či jen obličeje, hemihypertrofie/ hypotrofie, Blaschkovy linie v utváření pigmentací i kožních adnex, variabilita projevů je rozsáhlá. 7) Nositelé mozaiek mají zvýšené riziko malignit jako většina chromozomálních aberací, chromozomální instability, ale i hamartomatóz. 8) U genových mozaik je mentální vývoj obvykle normální a projevy se omezují na zevní abnormity. 9) Výskyt mozaikových fenotypů je dosti častý a jejich diagnostika je významná pro hodnocení klinické i genetické prognózy.

1) Mosaicism results from the mutation in part of somatic cells after the fertilization, only a few cases occur due to mutation during meiosis. Mosaicism is characterized by genetic or functional difference of two or more cell lines in one individual from one zygote. 2) Phenotypical variety is high and depends on the proportion of cell lines of individual clones. 3) Clinical prognosis of mosaic individuum is better in comparison to the full mutation in all cells. 4) The genetic prognosis of reproduction in relatives of the mosaic individuum is without increased recurrent risk, genetic prognosis of own offspring depends on the moment of mutation occurrence – wheit occurs before day 16 to 20 when gonadal cells are differentiated, it represents high risk of transmission. 5) Diagnosis of mixoploids in some cases requests investigation of different cells (fibroblasts, lymphocytes). 6) Clinical „signal“ features of the mosaic are hemihypertrophy, asymmetry, Blaschko lines, pigmentations. 7) Risk of malignant tumor is increased, similarly to other chromosomal aberrations, chromosomal instability or hamartomatoses. 8) Mosaics of gene mutation have usually normal mental development and are manifested by external abnormalities only. 9) Incidence of mosaic phenotypes is high and therefore the diagnosis of mixoploids and gene mosaic is important for the estimation of clinical as well as genetic prognosis.

• MeSH
• buněčné linie MeSH
• chromozomální aberace MeSH
• exprese genu MeSH
• fenotyp MeSH
• hodnocení rizik MeSH
• lidé MeSH
• mozaicismus MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• cystická fibróza patofyziologie   MeSH
• genetické jevy MeSH
• střevní sekrety MeSH
• vrozené, dědičné a novorozenecké nemoci a abnormality MeSH
• Publikační typ
• vysokoškolské kvalifikační práce MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• pneumologie a ftizeologie
• genetika, lékařská genetika

BACKGROUND: Brugada syndrome (BrS) is an inherited ion channelopathy that may predispose affected individuals to atrial cardiomyopathy. We tested the hypothesis that BrS patients have higher degrees of atrial electrophysiological abnormalities compared to controls, and these can be reflected by changes in P-wave parameters determined on the electrocardiogram (ECG). METHODS: This was a single-center retrospective study comparing BrS patients to age- and gender-matched control subjects. Mean P-wave duration (PWDmean), maximum PWD (PWDmax) and minimum PWD (PWDmin), P-wave dispersion (PWDmax - PWDmin), and P-wave terminal force in V1 (PTFV1) were measured. PWDmax ≥ 120 ms, in the presence and absence of biphasic P-waves in the inferior leads, were termed advanced and partial inter-atrial block (IAB), respectively. RESULTS: The proportion of IAB was significantly higher in BrS patients (28/51; 55%) than in control subjects (14/51; 27%; Fisher's Exact test; P < 0.01). Advanced IAB was observed in two BrS patients but none of the control subjects (P = 0.50). Compared to controls, BrS patients showed higher PWDmean (107 [98-113] vs. 97 [90-108] ms; KWANOVA, P < 0.01), PWDmax (123 [110-132] vs. 113 [107-121] ms; P < 0.001) but statistically indistinguishable PWDmin (82 [72-92] vs. 77 [69-85]; P = 0.09), and P-wave dispersion (38 [26-52] vs. 37 [23-45] ms; P = 0.14). PTFV1 was significantly higher in BrS patients than in control subjects (24 [0-40] vs. 0 [0-27] mm.ms; P < 0.05). CONCLUSION: Atrial conduction abnormalities are frequently observed in BrS. These patients may require monitoring for future development of atrial fibrillation and stroke.

• MeSH
• Brugadův syndrom * diagnóza   MeSH
• elektrokardiografie MeSH
• fenotyp MeSH
• fibrilace síní * diagnóza   MeSH
• lidé MeSH
• retrospektivní studie MeSH
• srdeční síně MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

• MeSH
• dítě MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• dystonické poruchy genetika   diagnóza   patofyziologie   komplikace   MeSH
• dystonie genetika   etiologie   patofyziologie   diagnóza   MeSH
• fenotyp * MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurovývojové poruchy genetika   diagnóza   MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

• MeSH
• abnormality zubů genetika   MeSH
• dentice MeSH
• ektodermální dysplazie genetika   MeSH
• finanční podpora výzkumu jako téma MeSH
• inbrední kmeny myší MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH

• MeSH
• chování MeSH
• duševní poruchy MeSH
• osobnost MeSH
• psychopatologie MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Psychopatologie
• NLK Obory
• behaviorální vědy
• psychiatrie

• MeSH
• dítě MeSH
• fenotyp MeSH
• karyotypizace MeSH
• lidské chromozomy MeSH
• mnohočetné abnormality MeSH
• Check Tag
• dítě MeSH
• Publikační typ
• kazuistiky MeSH

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.

• MeSH
• blefarofimóza diagnóza   genetika   MeSH
• dítě MeSH
• exony * MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• histonacetyltransferasy genetika   MeSH
• kongenitální hypotyreóza diagnóza   genetika   MeSH
• kraniofaciální abnormality diagnóza   genetika   MeSH
• ledviny abnormality   MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• nestabilita kloubu diagnóza   genetika   MeSH
• patela abnormality   MeSH
• psychomotorické poruchy diagnóza   genetika   MeSH
• sekvence nukleotidů MeSH
• skrotum abnormality   MeSH
• urogenitální abnormality diagnóza   genetika   MeSH
• vrozené srdeční vady diagnóza   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

BACKGROUND: Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD), intellectual disability/developmental delay (ID/DD), learning problems, language disorders, hyperactivity, and epilepsy. Correlation between this duplication and the carrier phenotype needs further discussion. METHODS: In this study, three unrelated patients with ID/DD and ASD underwent SNP aCGH and MLPA testing. Similarities in the phenotypes of patients with 9p24.3, 15q11.2, and 16p11.2 duplications were also observed. RESULTS: All patients with ID/DD and ASD carried the 9p24.3 duplication and showed intragenic duplication of DOCK8. Additionally, two patients had ADHD, one was hearing impaired and obese, and one had macrocephaly. Inheritance of the 9p24.3 duplication was confirmed in one patient and his sibling. In one patient KANK1 was duplicated along with DOCK8. Carriers of 9p24.3, 15q11.2, and 16p11.2 duplications showed several phenotypic similarities, with ID/DD more strongly associated with duplication of 9p24.3 than of 15q11.2 and 16p11.2. CONCLUSION: We concluded that 9p24.3 is a likely cause of ASD and ID/DD, especially in cases of DOCK8 intragenic duplication. DOCK8 is a likely causative gene, and KANK1 aberrations a modulator, of the clinical phenotype observed. Other modulators were not excluded.

• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• chromozomální poruchy genetika   patologie   MeSH
• cytoskeletální proteiny genetika   MeSH
• dítě MeSH
• duplikace chromozomů * MeSH
• fenotyp * MeSH
• lidé MeSH
• lidské chromozomy, pár 9 genetika   MeSH
• předškolní dítě MeSH
• výměnné faktory guaninnukleotidů genetika   MeSH
• vývojové poruchy u dětí genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Approximately 35 % of the mouse genes are indispensable for life, thus, global knock-out (KO) of those genes may result in embryonic or early postnatal lethality due to developmental abnormalities. Several KO mouse lines are valuable human disease models, but viable homozygous mutant mice are frequently required to mirror most symptoms of a human disease. The site-specific gene editing systems, the transcription activator-like effector nucleases (TALENs), Zinc-finger nucleases (ZFNs) and the clustered regularly interspaced short palindrome repeat-associated Cas9 nuclease (CRISPR/Cas9) made the generation of KO mice more efficient than before, but the homozygous lethality is still an undesired side-effect in case of many genes. The literature search was conducted using PubMed and Web of Science databases until June 30th, 2020. The following terms were combined to find relevant studies: "lethality", "mice", "knock-out", "deficient", "embryonic", "perinatal", "rescue". Additional manual search was also performed to find the related human diseases in the Online Mendelian Inheritance in Man (OMIM) database and to check the citations of the selected studies for rescuing methods. In this review, the possible solutions for rescuing human disease-relevant homozygous KO mice lethal phenotypes were summarized.

• MeSH
• CRISPR-Cas systémy genetika   MeSH
• editace genu metody   MeSH
• fenotyp MeSH
• myši knockoutované MeSH
• myši MeSH
• nukleasy s motivem zinkových prstů genetika   MeSH
• TALENs genetika   MeSH
• ztráta embrya genetika   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH