The genetic architecture of corneal endothelial dystrophies remains unknown in a substantial number of affected individuals. The proband investigated in the current study was diagnosed in the neonatal period with bilateral corneal opacification due to primary endothelial cell dysfunction. Neither his parents nor his sister had signs of corneal disease. Conventional karyotyping revealed a de novo translocation involving chromosomes 3 and 20, t(3;20)(q25;p11-12). Following genome and targeted Sanger sequencing analysis, the breakpoints were mapped at the nucleotide level. Notably, the breakpoint on chromosome 20 was identified to lie within the same topologically associated domain (TAD) as corneal endothelial dystrophy-associated gene OVOL2, and it is predicted to disrupt distal enhancers. The breakpoint at chromosome 3 is located within intron 2 of PFN2, which is currently not associated with any human disease. Further interrogation of the proband's genome failed to identify any additional potentially pathogenic variants in corneal endothelial dystrophy-associated genes. Disruption of a candidate cis-regulatory element and/or positional effects induced by translocation of OVOL2 to a novel genomic context may lead to an aberrant OVOL2 expression, a previously characterized disease mechanism of corneal endothelial dystrophy. Further research is necessary to explore how disruption of regulatory elements may elucidate genetically unsolved corneal endothelial dystrophies.

• MeSH
• dědičné dystrofie rohovky * genetika   diagnóza   MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• lidské chromozomy, pár 3 genetika   MeSH
• novorozenec MeSH
• regulační oblasti nukleových kyselin * MeSH
• rodokmen MeSH
• transkripční faktory * genetika   MeSH
• translokace genetická MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Ovol2 protein, human MeSH Prohlížeč
• transkripční faktory * MeSH

Chromosomal band 17q12 is a gene-rich region flanked by segmental duplications, making the region prone to deletions and duplications via the non-allelic homologous recombination mechanism. While deletions cause a well-described disorder with a specific phenotype called renal cysts and diabetes mellitus, the phenotype caused by reciprocal duplications is less specific, primarily because of variable expressivity, and incomplete penetrance. We present an unusual family with four children carrying the 17q12 microduplication inherited from their clinically healthy mother, who was a carrier of both the duplication and, interestingly, also of an atypical deletion of the 17q12 region. The duplication was inherited from her diabetic father and the deletion from her diabetic mother who also suffered from a renal disorder. Clinical manifestations in the family were variable, but all children showed some degree of a neurodevelopmental disorder, such as epilepsy, intellectual disability, delayed speech development, or attention deficit disorder. The simultaneous occurrence of a deletion and duplication in the same chromosomal region in one family is very rare, and to our knowledge, individuals carrying both a deletion and a duplication of this region have never been described.

• Klíčová slova
• 17q12 deletion, 17q12 duplication, LHX1 gene, epilepsy, intellectual disability,
• MeSH
• chromozomální delece MeSH
• duplikace chromozomů genetika   MeSH
• fenotyp MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• mnohočetné abnormality * genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: With only 11 patients reported, 5p tetrasomy belongs to rare postnatal findings. Most cases are due to small supernumerary marker chromosomes (sSMCs) or isochromosomes. The patients share common but unspecific symptoms such as developmental delay, seizures, ventriculomegaly, hypotonia, and fifth finger clinodactyly. Simple interstitial duplications leading to trisomies of parts of 5p are much more frequent and better described. Duplications encompassing 5p13.2 cause a defined syndrome with macrocephaly, distinct facial phenotype, heart defects, talipes equinovarus, feeding difficulties, respiratory distress and anomalies of the central nervous system, developmental delay and hypotonia. CASE PRESENTATION: We present a boy with dysmorphic features, developmental delay, intellectual disability and congenital anomalies, and a mosaic sSMC inv dup(5)(p15.33p15.1). He is the fourth and the oldest reported patient with distal 5p tetrasomy. His level of mosaicism was significantly different in lymphocytes (13.2%) and buccal cells (64.7%). The amplification in our patient is smaller than that in the three previously published patients but the only phenotype difference is the absence of seizures in our patient. CONCLUSIONS: Our observations indicate that for the assessment of prognosis, especially with respect to intellectual functioning, the level of mosaicism could be more important than the extent of amplification and the number of extra copies. Evaluation of the phenotypical effect of rare chromosomal aberrations is challenging and each additional case is valuable for refinement of the genotype-phenotype correlation. Moreover, our patient demonstrates that if the phenotype is severe and if the level of sSMC mosaicism is low in lymphocytes, other tissues should be tested.

• Klíčová slova
• 5p tetrasomy, Intellectual disability, Marker chromosome, Mosaicism,
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Analyses at nucleotide resolution reveal unexpected complexity of seemingly simple and balanced chromosomal rearrangements. Chromothripsis is a rare complex aberration involving local shattering of one or more chromosomes and reassembly of the resulting DNA segments. This can influence gene expression and cause abnormal phenotypes. We studied the structure and mechanism of a seemingly balanced de novo complex rearrangement of four chromosomes in a boy with developmental and growth delay. Microarray analysis revealed two paternal de novo deletions of 0.7 and 2.5 Mb at two of the breakpoints in 1q24.3 and 6q24.1-q24.2, respectively, which could explain most symptoms of the patient. Subsequent whole-genome mate-pair sequencing confirmed the chromothriptic nature of the rearrangement. The four participating chromosomes were broken into 29 segments longer than 1 kb. Sanger sequencing of all breakpoint junctions revealed additional complexity compatible with the involvement of different repair pathways. We observed translocation of a 33 bp long DNA fragment, which may have implications for the definition of the lower size limit of structural variants. Our observations and literature review indicate that even very small fragments from shattered chromosomes can be detected and handled by the repair machinery during germline chromothriptic chromosome reassembly.

• Klíčová slova
• DNA repair, alternative non-homologous end joining, chromothripsis, complex chromosome aberration, small insertions, whole-genome sequencing,
• MeSH
• chromothripsis * MeSH
• DNA genetika   MeSH
• dospělí MeSH
• karyotyp MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• mladiství MeSH
• novorozenec MeSH
• oprava DNA * MeSH
• předškolní dítě MeSH
• sekvence nukleotidů MeSH
• zárodečné buňky metabolismus   MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH

Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient's death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1.

• Klíčová slova
• BRCA2, FANCD1, Fanconi anemia, Leukemia, Medulloblastoma, Wilms tumor,
• MeSH
• Fanconiho anemie diagnóza   farmakoterapie   genetika   MeSH
• fenotyp MeSH
• hybridizace in situ fluorescenční MeSH
• imunofenotypizace MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• předškolní dítě MeSH
• protein BRCA2 genetika   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• rodina MeSH
• ztráta heterozygozity MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protein BRCA2 MeSH

We identified a de novo deletion of 14q11.2 in a Czech patient with developmental delay, mild autistic features, macrosomy, macrocephaly, orthognathic deformities, and dysmorphic facial features. The clinical follow-up of the patient lasting 14 years documented changes in the facial dysmorphism from infancy to adolescence. The deletion affects approximately 200 kb of DNA with five protein-coding genes and two snoRNA genes. Two of the protein-coding genes, SUPT16H and CHD8, have been proposed as candidate genes for a new microdeletion syndrome. Our patient further supports the existence of this syndrome and extends its phenotypic spectrum, especially points to the possibility that orthognathic deformities may be associated with microdeletions of 14q11.2. CHD8 mutations have been found in patients with neurodevelopmental disorders and macrocephaly. The HNRNPC gene, repeatedly deleted in patients with developmental delay, is another candidate as its 5́ end is adjacent to the deletion, and the expression of this gene may be affected by position effect.

• Klíčová slova
• CHD8, Microdeletion 14q11.2, SUPT16H, intellectual disability, macrocephaly, orthognathic deformities,
• MeSH
• chromozomální delece * MeSH
• DNA vazebné proteiny genetika   MeSH
• lidé MeSH
• lidské chromozomy, pár 14 genetika   MeSH
• megalencefalie diagnóza   genetika   MeSH
• mentální retardace diagnóza   genetika   MeSH
• mladiství MeSH
• mnohočetné abnormality diagnóza   genetika   MeSH
• následné studie MeSH
• transkripční faktory genetika   MeSH
• vývojové poruchy u dětí diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CHD8 protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• transkripční faktory MeSH

BACKGROUND: Inversions are balanced structural chromosome rearrangements, which can influence gene expression and the risk of unbalanced chromosome constitution in offspring. Many examples of inversion polymorphisms exist in human, affecting both heterochromatic regions and euchromatin. RESULTS: We describe a novel, 15 Mb long paracentric inversion, inv(21)(q21.1q22.11), affecting more than a third of human 21q. Despite of its length, the inversion cannot be detected using karyotyping due to similar band patterns on the normal and inverted chromosomes, and is therefore likely to escape attention. Its identification was aided by the repeated observation of the same pair of 150 kb long duplications present in cis on chromosome 21 in three Czech families subjected to microarray analysis. The finding prompted us to hypothesise that this co-occurrence of two remote duplications could be associated with an inversion of the intervening segment, and this speculation turned out to be right. The inversion was confirmed in a series of FISH experiments which also showed that the second copy of each of the duplications was always located at the opposite end of the inversion. The presence of the same pair of duplications in additional individuals reported in public databases indicates that the inversion may also be present in other populations. Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660. Although the breakpoints affect protein-coding genes, the occurrence of the inversion in normal parents and siblings of our patients and the occurrence of the duplications in unaffected controls in databases indicate that this rare variant is rather non-pathogenic. The inverted segment carried an identical shared haplotype in the three families studied. The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion. CONCLUSIONS: The identification of inv(21)(q21.1q22.11) supports the notion that paracentric inversions are the most common form of chromosomal variation and that some of them may still remain undetected.

• Klíčová slova
• Duplication, Founder effect, Inversion, SNP arrays, USP25,
• Publikační typ
• časopisecké články MeSH

Developmental delay is often a predictor of mental retardation (MR) or autism, two relatively frequent developmental disorders severely affecting intellectual and social functioning. The causes of these conditions remain unknown in most patients. They have a strong genetic component, but the specific genetic defects can only be identified in a fraction of patients. Recent developments in genomics supported the establishment of the causal link between copy number variants in the genomes of some patients and their affection. One of the techniques suitable for this analysis is array comparative genome hybridization, which can be used both for detailed mapping of chromosome rearrangements identified by classical cytogenetics and for the identification of novel submicroscopic gains or losses of genetic material. We illustrate the power of this approach in two patients. Patient 1 had a cytogenetically visible deletion of chromosome X and the molecular analysis was used to specify the gene content of the deletion and the prognosis of the child. Patient 2 had a seemingly normal karyotype and the analysis revealed a small recurrent deletion of chromosome 1 likely to be responsible for his phenotype. However, the genetic dissection of MR and autism is complicated by high heterogeneity of the genetic aberrations among patients and by broad variability of phenotypic effects of individual genetic defects.

• MeSH
• chromozomální delece * MeSH
• dítě MeSH
• genetické nemoci vázané na chromozom X genetika   MeSH
• genom lidský * MeSH
• lidé MeSH
• lidské chromozomy X genetika   MeSH
• lidské chromozomy, pár 1 genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• srovnávací genomová hybridizace * MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

We describe a girl with neurofibromatosis type 1 (NF1), mild dysmorphic features, growth and mental retardation, autism, and mosaicism of ring chromosome 17 and chromosome 17 monosomy. The extent of genetic material deleted from the ring chromosome was determined using a combination of classical cytogenetics, fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) to be 0.6-2.5 Mb on 17p, and up to about 10 Mb on 17q. Based on our observations and on a review of the literature we argue that in addition to a universal "ring syndrome" which is based on ring instability and is less specific for the chromosome involved, various ring chromosomes underlie their own characteristic phenotypes. We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells. A similar mechanism or a direct involvement of respective disease genes in the aberration could possibly influence also the development of autism and other symptoms. We raise a question if the loss of one copy of chromosome 17 from a substantial fraction of somatic cells can have specific consequences also for future risks of the patient, for example, due to the mosaic hemizygosity for the BRCA1 and TP53 genes.

• MeSH
• autistická porucha komplikace   diagnóza   genetika   MeSH
• dítě MeSH
• hybridizace in situ fluorescenční MeSH
• kruhové chromozomy * MeSH
• lidé MeSH
• lidské chromozomy, pár 17 genetika   MeSH
• mozaicismus * MeSH
• neurofibromatóza 1 komplikace   diagnóza   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

OBJECTIVES: In contrast to most human autosomal genes which are expressed biallelically, the expression of imprinted genes depends on the parental origin of the allele. Prader-Willi syndrome is a neurobehavioral disorder in which the expression of active paternal alleles of imprinted genes from chromosomal region 15q11-q13 is abolished by deletions, maternal uniparental disomy or imprinting defects. We report an unusual case of maternal uniparental disomy of chromosome 15 due to a balanced translocation t(8;15)(q24.1;q21.2) leading to Prader-Willi syndrome in a 3-year-old girl. METHODS AND RESULTS: Cytogenetic investigation revealed a balanced translocation t(8;15)(q24.1;q21.2) in the patient and subsequently also in her unaffected mother. Fluorescence in situ hybridization analysis did not reveal any deletion of the PWS critical region, but methylation analysis of the SNRPN gene showed an abnormal methylation pattern indicating the absence of paternal chromosome 15. Microsatellite analysis of multiple loci and methylation-specific MLPA analysis confirmed maternal uniparental heterodisomy of chromosome 15 as the cause of PWS in the patient. CONCLUSIONS: This example emphasizes the importance of uniparental disomy testing in pregnancies of carriers of chromosomal aberrations with participation of chromosomes carrying imprinted genes involved in human diseases.

• MeSH
• cytogenetické vyšetření MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• lidské chromozomy, pár 15 MeSH
• lidské chromozomy, pár 8 MeSH
• metylace DNA MeSH
• mikrosatelitní repetice MeSH
• Praderův-Williho syndrom genetika   MeSH
• předškolní dítě MeSH
• translokace genetická * MeSH
• uniparentální disomie genetika   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH