The human genome contains approximately 20,000 protein-coding genes, of which more than 15,000 (3/4) are expressed, among others, in the central nervous system. Variants that damage the function of these genes (called pathogenic variants) can lead to various forms of neurodevelopmental disorders (NDD), including speech and language disorders. These can occur alone or in various combinations. In this review article, we provide information on the possibilities, limits and importance of genetic testing in patients with NDD.
- MeSH
- genetická variace MeSH
- genetické nemoci vrozené diagnóza genetika MeSH
- genetické testování metody MeSH
- lidé MeSH
- mnohočetné abnormality diagnóza genetika MeSH
- mutace MeSH
- neurovývojové poruchy * diagnóza etiologie genetika MeSH
- vývojové poruchy řeči diagnóza etiologie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- diferenciální diagnóza MeSH
- epilepsie benigní neonatální * diagnóza etiologie farmakoterapie klasifikace MeSH
- lidé MeSH
- novorozenec MeSH
- prenatální diagnóza MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
Epilepsie jsou heterogenní skupinou onemocnění s významným etiologickým podílem patogenních variant v genech exprimovaných v centrálním nervovém systému. Monogenní epilepsie jsou jednotlivě vzácné, prevalence většiny z nich je neznámá, ale pravděpodobně je u většiny menší než 1 : 10 000. Prognózu mají různou v závislosti na postiženém genu a typu patogenní varianty. Ozřejmění genetické příčiny epilepsie může vést nejen ke stanovení rizika opakování epilepsie v rodině, ale v některých případech také k optimalizaci protizáchvatové medikace. V přehledovém článku přinášíme informace o vzácných geneticky podmíněných epilepsiích, u nichž může znalost patogenní varianty přispět k optimalizaci léčby.
Epilepsies are heterogeneous group of diseases with a significant etiological role of pathogenic variants in the genes expressed in the central nervous system. Monogenic epilepsies are individually rare, prevalence of most of them is unknown, but it is probably less than 1 : 10000. The outcome is variable, depending on the affected gene and type of the variant. The identification of the genetic causes of epilepsy can not only determine the risk of recurrence of epilepsy in the family, but in some cases also to optimize anti-seizure medication. In the overview article, we bring information about rare genetically conditioned epilepsies, in which knowledge of the pathogenic variant may contribute to the optimization of treatment.
- Klíčová slova
- cílená protizáchvatová terapie, gen PRRT2,
- MeSH
- aldehyddehydrogenasa genetika MeSH
- antikonvulziva klasifikace terapeutické užití MeSH
- cílená molekulární terapie MeSH
- draslíkové kanály KCNQ genetika MeSH
- epilepsie * diagnóza genetika terapie MeSH
- genetické nemoci vrozené MeSH
- hamartin genetika MeSH
- lidé MeSH
- napětím řízený sodíkový kanál, typ 1 genetika MeSH
- přenašeč glukosy typ 1 genetika MeSH
- sodíkové kanálky řízené napětím genetika MeSH
- tuberin genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- vzácné nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far. METHODS: We studied a 12-year-old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed. RESULTS: ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations. CONCLUSION: Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype-phenotype correlation in CMS20.
- MeSH
- genetické asociační studie MeSH
- heterozygot MeSH
- kongenitální myastenické syndromy * genetika diagnóza MeSH
- lidé MeSH
- mentální retardace * komplikace MeSH
- missense mutace MeSH
- symportéry * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem 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
Chromosome 17q21.31 microdeletion syndrome is a genomic disorder caused by a recurrent 600 kb long deletion. The deletion affects the region of a common inversion present in about 20% of Europeans. The inversion is associated with the H2 haplotype carrying additional low-copy repeats susceptible to non-allelic homologous recombination, and this haplotype is prone to deletion. No instances of 17q21.31 deletions inherited from an affected parent have been reported, and the deletions always affected a parental chromosome with the H2 haplotype. The syndrome is characterized clinically by intellectual disability, hypotonia, friendly behavior and specific facial dysmorphism with long face, large tubular or pear-shaped nose and bulbous nasal tip. We present monozygotic twin sisters showing the typical clinical picture of the syndrome. The phenotype of the sisters was very similar, with a slightly more severe presentation in Twin B. The 17q21.31 microdeletion was confirmed in both patients but in neither of their parents. Potential copy number differences between the genomes of the twins were subsequently searched using high-resolution single nucleotide polymorphism (SNP) and comparative genome hybridisation (CGH) arrays. However, these analyses identified no additional aberrations or genomic differences that could potentially be responsible for the subtle phenotypic differences. These could possibly be related to the more severe perinatal history of Twin B, or to the variable expressivity of the disorder. In accord with the expectations, one of the parents (the mother) was shown to carry the H2 haplotype, and the maternal allele of chromosome 17q21.31 was missing in the twins.
- MeSH
- chromozomální delece MeSH
- dospělí MeSH
- dvojčata monozygotní genetika MeSH
- haplotypy * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- lidské chromozomy, pár 17 genetika MeSH
- mentální retardace genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- studie na dvojčatech MeSH
Proximal 6q deletions have a milder phenotype than middle and distal 6q deletions. We describe 2 patients with non-overlapping deletions of about 15 and 19 Mb, respectively, which subdivide the proximal 6q region into 2 parts. The aberrations were identified using karyotyping and analysed using mBAND and array CGH. The unaffected mother of the first patient carried a mosaic karyotype with the deletion in all metaphases analysed and a small supernumerary marker formed by the deleted material in about 77% of cells. Her chromosome 6 centromeric signal was split between the deleted chromosome and the marker, suggesting that this deletion arose through the centromere fission mechanism. In this family the location of the proximal breakpoint in the centromere prevented cloning of the deletion junction, but the junction of the more distal deletion in the second patient was cloned and sequenced. This analysis showed that the latter aberration was most likely caused by non-homologous end joining. The second patient also had a remarkably more severe phenotype which could indicate a partial overlap of his deletion with the middle 6q interval. The phenotypes of both patients could be partly correlated with the gene content of their deletions and with phenotypes of other published patients.
- MeSH
- chromozomální delece MeSH
- fenotyp MeSH
- genetické asociační studie MeSH
- hybridizace in situ fluorescenční MeSH
- karyotyp MeSH
- kojenec MeSH
- lidé MeSH
- lidské chromozomy, pár 6 genetika MeSH
- předškolní dítě MeSH
- pruhování chromozomů MeSH
- srovnávací genomová hybridizace MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
