Kongenitálna adrenálna hypoplázia (AHC) je X-viazané ochorenie, charakteristické soľnou poruchou krátko po narodení, primárnou adrenálnou insuficienciou v detstve a chýbajúcim nástupom puberty v dôsledku hypogonadotropného hypogonadizmu (HH). Doteraz popísané mutácie DAX-1 génu u pacientov s AHC a HH zahŕňajú substitúcie nukleotidov (missense/nonsense), malé delécie, inzercie a indely, veľké delécie ako aj komplexné preskupenia. V práci popisujeme klinické príznaky, výsledky laboratórnych a hormonálnych vyšetrení a výsledky molekulárnej analýzy u mužského probanda so suspektnou X-viazanou AHC. Sekvenčná analýza u pacienta potvrdila inzerciu dvoch nukleotidov (cytozínu a guanínu) v kodóne 141 prvého exónu DAX-1 génu. Mutácia viedla k úplne odlišnému sledu aminokyselín od kodónu 141 až do predčasného stop kodónu ACT na pozícii 177. Podľa očakávania, matka pacienta bola heterozygotnou prenášačkou mutácie, zatiaľ čo sestra pacienta je zdravá. Prípad zdôrazňuje význam genetického testovania pacientov s primárnou adrenálnou insuficienciou a podozrením na X-viazanú formu AHC. Príznačným je nález hoci i parciálneho deficitu gonadotropínov u postihnutých mužských pacientov. Skoré rozpoznanie diagnózy AHC u pacienta, ktoré môže byť potvrdené analýzou na prítomnosť mutácie v DAX-1 géne, je dôležité pre predchádzanie následkov oneskorenej substitučnej liečby androgénmi, ako aj pre genetické poradenstvo v postihnutej rodine.

Adrenal hypoplasia congenita (AHC) is an X-linked disorder, characterized by salt-losing crisis in the neonatal period, primary adrenal insufficiency during infancy and failure to undergo puberty because of hypogonadotropic hypogonadism (HH). Different mutations types of the DAX-1 gene have been reported in patients with AHC and HH, including nucleotide substitutions (missense/nonsense), small deletions, insertions and indels, gross deletions as well as complex rearrangements. In this report, we describe the clinical features, the laboratory and hormonal findings and the results of mutational analysis in proband male patient with suspected X-linked AHC. Sequence analysis of the patient´s DAX-1 gene demonstrated a 2-bp (CG) insertion at codon 141 in exon 1. The mutation shifts the reading frame, resulting in completely different amino acid sequences from codon 141 to the premature stop codon ACT at amino acid 177. As expected, the patient´s mother was a heterozygous carrier for the mutation, whereas his sister did not carry the mutation. This case emphasizes the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC. The findings of even partial gonadotropic deficiency in the affected males is notable and early recognition of such a possibility in a patient, which may be facilated by DAX-1 mutational analysis, may help to prevent the sequelee of delayed androgen replacement therapy, as well as for genetic counseling in the affected family.

• MeSH
• adrenální insuficience diagnóza   patologie   terapie   MeSH
• dospělí MeSH
• genetické nemoci vrozené diagnóza   patologie   terapie   MeSH
• hypogonadismus genetika   patologie   terapie   MeSH
• lidé MeSH
• mutace MeSH
• nemoci varlat patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• Fanconiho anemie * MeSH
• lidé MeSH
• nádory prsu MeSH
• posunová mutace MeSH
• protein FANCL genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• práce podpořená grantem MeSH

De novo sequence variants, including truncating and splicing variants, in the additional sex‑combs like 3 gene (ASXL3) have been described as the cause of Bainbridge‑Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi‑step molecular diagnostics algorithm, including karyotype and array‑comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next‑generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene‑rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.

• MeSH
• dítě MeSH
• lidé MeSH
• mikrocefalie genetika   MeSH
• pilotní projekty MeSH
• poruchy řeči genetika   MeSH
• posunová mutace MeSH
• rodokmen MeSH
• svalová hypotonie genetika   MeSH
• transkripční faktory genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Spinocerebellar ataxia type 28 (SCA28) is an autosomal dominant neurodegenerative disorder caused by missense AFG3L2 mutations. To examine the occurrence of SCA28 in the Czech Republic, we screened 288 unrelated ataxic patients with hereditary (N = 49) and sporadic or unknown (N = 239) form of ataxia for mutations in exons 15 and 16, the AFG3L2 mutation hotspots. A single significant variant, frameshift mutation c.1958dupT leading to a premature termination codon, was identified in a patient with slowly progressive speech and gait problems starting at the age of 68 years. Neurological examination showed cerebellar ataxia, mild Parkinsonian features with predominant bradykinesia, polyneuropathy of the lower limbs, and cognitive decline. However, other common SCA28 features like pyramidal tract signs (lower limb hyperreflexia, positive Babinski sign), ophthalmoparesis or ptosis were absent. The mutation was also found in a patient's unaffected daughter in whom a targeted examination at 53 years of age revealed mild imbalance signs. RNA analysis showed a decreased ratio of the transcript from the mutated AFG3L2 allele relative to the normal transcript in the peripheral lymphocytes of both patients. The ratio was increased by puromycin treatment, indicating that the mutated transcript can be degraded via nonsense-mediated RNA decay. The causal link between the mutation and the phenotype of the patient is currently unclear but a pathogenic mechanism based on AFG3L2 haploinsufficiency rather than the usual dominant-negative effect of missense AFG3L2 mutations reported in SCA28, cannot be excluded.

• MeSH
• fenotyp MeSH
• genetická predispozice k nemoci genetika   MeSH
• lidé MeSH
• oftalmoplegie genetika   MeSH
• posunová mutace genetika   MeSH
• proteasy závislé na ATP genetika   MeSH
• senioři MeSH
• spinocerebelární ataxie diagnóza   genetika   MeSH
• spinocerebelární degenerace genetika   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non-consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome.

• MeSH
• adaptorový proteinový komplex 4 genetika   MeSH
• dítě MeSH
• kvadruplegie diagnóza   genetika   MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   MeSH
• mladiství MeSH
• posunová mutace * MeSH
• sourozenci MeSH
• syndrom MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mutations in the insulin (INS) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A-chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood-onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes.

• MeSH
• C-peptid genetika   MeSH
• diabetes mellitus 2. typu genetika   MeSH
• dospělí MeSH
• inzulin genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• posunová mutace genetika   MeSH
• rodina MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA 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
• kazuistiky MeSH
• práce podpořená grantem MeSH

Several subsets of patients with hereditary spherocytosis (HS) have been defined based on the specific red blood cell membrane protein deficiencies involving spectrin, ankyrin, band 3, and protein 4.2. Mutations of the genes encoding these proteins are currently being uncovered. Regarding spectrin, only three isolated cases of beta-spectrin gene mutations were recently reported in association with HS and spectrin deficiency. We have screened the coding region of the beta-spectrin gene using the SSCP technique, in 40 families with HS associated with spectrin deficiency or combined spectrin and ankyrin deficiencies. In this report we describe six frameshift and nonsense mutations and four missense mutations of the beta-spectrin gene in 11 unrelated families. Taking advantage of modifications in the restriction enzyme recognition sequences introduced by the mutations, we show, in all cases of frameshift and nonsense mutations, the loss of heterozygosity at the cDNA level when compared to genomic DNA, reflecting the absence of the mutant mRNA transcripts. In one family with a large pedigree including six generations and 112 members, we firmly establish the autosomal dominant inheritance of one of the beta-spectrin null mutations. Most of the mutations described are responsible for a phenotype of mild to moderate autosomal dominant form of HS associated with a conspicuous spherocytosis with frequent spiculated cells (8% to 15% acanthocytes). One missense mutation appears to be associated with a recessive form of the disease. Five common restriction enzyme polymorphisms of the coding region of the beta-spectrin gene are also described. Overall, these findings underscore the importance of the beta-spectrin gene mutations in the pathogenesis of HS and reemphasizes the extreme heterogeneity of the underlying molecular basis of this condition.

• MeSH
• dědičná sférocytóza * genetika   metabolismus   MeSH
• komplementární DNA genetika   MeSH
• lidé MeSH
• posunová mutace MeSH
• rodokmen MeSH
• spektrin genetika   nedostatek   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Bread wheat (Triticum aestivum) inflorescences, or spikes, are characteristically unbranched and normally bear one spikelet per rachis node. Wheat mutants on which supernumerary spikelets (SSs) develop are particularly useful resources for work towards understanding the genetic mechanisms underlying wheat inflorescence architecture and, ultimately, yield components. Here, we report the characterization of genetically unrelated mutants leading to the identification of the wheat FRIZZY PANICLE (FZP) gene, encoding a member of the APETALA2/Ethylene Response Factor transcription factor family, which drives the SS trait in bread wheat. Structural and functional characterization of the three wheat FZP homoeologous genes (WFZP) revealed that coding mutations of WFZP-D cause the SS phenotype, with the most severe effect when WFZP-D lesions are combined with a frameshift mutation in WFZP-A. We provide WFZP-based resources that may be useful for genetic manipulations with the aim of improving bread wheat yield by increasing grain number.

• MeSH
• fenotyp MeSH
• genetické lokusy genetika   MeSH
• květy genetika   růst a vývoj   MeSH
• posunová mutace genetika   fyziologie   MeSH
• pšenice genetika   růst a vývoj   fyziologie   MeSH
• rostlinné geny genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pyruvate kinase (PK) deficiency is an iron-loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease-causing PKLR mutations. Two of these mutations - the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) - have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease-causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK-deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor-15, were increased in PK-deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as-yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.

• MeSH
• dítě MeSH
• dospělí MeSH
• erytropoéza MeSH
• ferritiny krev   MeSH
• hemolytická nesférocytická kongenitální anemie krev   genetika   MeSH
• hepcidiny biosyntéza   krev   MeSH
• kojenec MeSH
• krevní transfuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• novorozenec MeSH
• potransfuzní reakce MeSH
• předškolní dítě MeSH
• přetížení železem genetika   MeSH
• pyruvátkinasa krev   nedostatek   genetika   MeSH
• sekvence aminokyselin MeSH
• sekvenční analýza DNA MeSH
• vrozené poruchy metabolismu pyruvátu krev   genetika   MeSH
• železo krev   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (STK11) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS. METHODS: We examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of STK11 gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of STK11 gene. RESULTS: We found pathogenic mutations in STK11 gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in STK11 gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far. CONCLUSION: Our results showed that a germline mutation of STK11 gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of STK11 gene.

• MeSH
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• Peutzův-Jeghersův syndrom genetika   MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy genetika   MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH