Vrozené vývojové vady postihují v České republice přibližně 3–5 % novorozených dětí. Vrozené vady kůže patří k těm nejméně častým typům, celkově tvoří méně než 5 % všech případů vrozených vývojových vad u narozených dětí. V rámci širšího projektu, zaměřeného na analýzu poměru pohlaví u vrozených vývojových vad, jsme se soustředili i na poměr pohlaví u vrozených vývojových vad kůže u dětí narozených v České republice mezi roky 1994 a 2017. V tomto období bylo zachyceno 5 187 dětí s vrozenými vývojovými vadami kůže, z toho bylo 2 668 dívek (51,4 %) a 2 518 chlapců (48,5 %). Výsledný poměr pohlaví M/F (male to female) je 0,94; byla tedy nalezena mírná převaha dívek. Skupina vrozených vývojových vad kůže je ovšem etiologicky velmi heterogenní a výsledky je potřeba vnímat v tomto kontextu.
Congenital anomalies affect approximately 3-5% of newborns in the Czech Republic. Congenital skin defects are among the least common types, accounting for less than 5% of all congenital anomalies ́ cases in newborns. As part of a broader project focused on the analysis of the sex ratio in congenital anomalies, we also focused on the gender ratio in congenital anomalies of the skin in children born in the Czech Republic between 1994 and 2017. During this period, 5,187 children with congenital anomalies of the skin were recorded, of which there were 2668 girls (51.4%) and 2518 boys (48.5%). The resulting gender ratio M/F (male to female) is 0.94, so a slight predominance of girls was found. However, the congenital anomalies of the skin group are etiologically very heterogeneous and the results need to be seen in this context.
INTRODUCTION: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies. MATERIALS AND METHODS: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members. RESULTS: In total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%). CONCLUSION: These two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.
- Publikační typ
- časopisecké články MeSH
Bloomův syndrom je vzácné onemocnění charakterizované prenatální i postnatální růstovou retardací, mikrocefalií, výrazně zvýšenou predispozicí k malignitám a kožními projevy. Postižení mají zvýšenou fotosenzitivitu se zarudnutím kůže po expozici slunečnímu záření, kožní skvrny café au lait i hypopigmentované oblasti. Bloomův syndrom je autozomálně recesivní dědičné onemocnění podmíněné mutacemi v obou alelách genu BLM. Naše kazuistika popisuje případ dítěte s molekulárně geneticky prokázanou homozygotní mutací v genu BLM: NM_000057.4: c.2643G>A, p.Trp881Ter.
Bloom syndrome is a rare condition characterized by prenatal and postnatal growth restriction, microcephaly, significantly increased cancer predisposition and skin changes. Affected individuals have increased photosensitivity, a skin rash exacerbated by sun exposure, café au lait macules and areas of skin hypopigmentation. Bloom syndrome is an autosomal recessive genetic disease caused by mutations of both alleles of BLM gene. Our case report describes a case of a child with homozygous pathogenic variants in BLM gene: NM_000057.4: c.2643G>A, p.Trp881Ter identified on molecular genetic testing level.
- MeSH
- Bloomův syndrom * dějiny diagnóza genetika patologie terapie MeSH
- diferenciální diagnóza MeSH
- efekt zakladatele MeSH
- kožní manifestace MeSH
- lidé MeSH
- mutace MeSH
- nádory etiologie MeSH
- poruchy růstu etiologie MeSH
- předškolní dítě MeSH
- vzácné nemoci dějiny diagnóza genetika patologie terapie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
Východiska: Poškození DNA ionizujícím zářením je hlavním mechanizmem účinku radioterapie (RT) a výsledek léčby a poradiační toxicitu zdravých tkání ovlivňuje řada faktorů zevních a vnitřních, mezi které patří i mutace v genech pro reparaci DNA vedoucí k různým poruchám rozpoznávání poškozené DNA a jejich oprav. Poruchy reparace DNA se mohou projevovat zvýšenou citlivostí k onkologické léčbě. Cíl: Mechanizmus opravy DNA a přehled genetických syndromů s mutacemi genů účastnících se reparace DNA objasňuje urychlenou kancerogenezi a zvýšenou radiosenzitivitu při RT nádorových onemocnění. Většina radiosenzitivních syndromů je autozomálně recesivně dědičná, příkladem jsou ataxia teleangiectasia, Nijmegenský syndrom lomivosti, xeroderma pigmentosum, Cockaynův syndrom, Bloomův syndrom a Wernerův syndrom. Závěr: Radioterapie je u většiny homozygotních pacientů s recesivními radiosenzitivními syndromy kontraindikována. Asymptomatičtí heterozygoti mohou mít zvýšené riziko vzniku nádorů a malá část pacientů i mírně zvýšené riziko intolerance RT, nicméně indikaci k RT to nelimituje. Vysoké riziko sekundárních malignit po radioterapii je kontraindikací adjuvantní RT u Li-Fraumeniho syndromu.
Background: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment. Purpose: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome. Conclusion: Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.
- MeSH
- Cockayneův syndrom genetika MeSH
- lidé MeSH
- mutace MeSH
- oprava DNA genetika MeSH
- tolerance záření * genetika MeSH
- xeroderma pigmentosum genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main drawback in a routine gene-by-gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next-generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD-related genes. Pathogenic or probably pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease-causing variants were detected in 23 genes. In addition, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high-clinical yield and should therefore be the preferred first-tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.
- MeSH
- dospělí MeSH
- genetické testování * MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- nemoci svalů epidemiologie genetika patofyziologie MeSH
- sekvenční analýza DNA * MeSH
- svalové dystrofie epidemiologie genetika patofyziologie MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
BACKGROUND: Constitutional translocations between sex chromosomes are rather rare in humans with breakpoints at Xp11 and Yq11 as the most frequent. Breakpoints on the short arm of the Y chromosome form one subgroup of t(X;Y), giving rise to a derived chromosome with the centromeres of both the X and Y chromosomes, dic(X;Y). Here, we report a rare congenital chromosomal aberration, 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10], in an adult male. CASE PRESENTATION: Primary myelofibrosis, a malignant haematological disease, was diagnosed in a 63-year-old man following liver transplantation after hepatocellular carcinoma. By the analysis of the bone marrow sample, the karyotype 46,X,dic(X;Y)(p22.33;p11.32) was detected in all the mitoses analysed and verified with multicolour fluorescence in situ hybridization (mFISH). A cytogenetic examination of stimulated peripheral blood cells revealed the constitutional karyotype 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10]. The cell line 45,X was confirmed with FISH in 35 % of interphase nuclei. The SRY locus was present on the dicentric chromosome. A CGH/SNP array (Illumina) revealed a gain of 153,7 Mbp of the X chromosome and a 803-kbp microdeletion (including the SHOX gene), which were also confirmed with FISH. SHOX encodes a transcriptional factor that regulates the growth of the long bones. The deletion of the SHOX gene together with the Madelung deformity of the forearm and the short stature of the proband led to a diagnosis of Léri-Weill dyschondrosteosis (LWD). The gain of almost the whole X chromosome (153,7 Mbp) was considered a variant of Klinefelter syndrome (KS). The levels of gonadotropins and testosterone were consistent with gonadal dysfunction. A malformation of the right external ear was detected. CONCLUSIONS: We have reported a structural aberration of the sex chromosomes, dic(X;Y)(p22.33;p11.32). The related genomic imbalance is associated with two known hereditary syndromes, LWD and a KS variant, identified in our proband at an advanced age. Because the breakpoints did not involve cancer genes, we inferred that the two malignancies in the proband were not caused by this abnormality. The possible influence of SHOX haploinsufficiency on the growth regulation of auricular chondrocytes is discussed.
- Publikační typ
- časopisecké články MeSH
The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.
- MeSH
- epilepsie genetika MeSH
- fenotyp MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- mutace * MeSH
- nemoci mozku genetika MeSH
- protein-serin-threoninkinasy genetika MeSH
- Rettův syndrom genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
