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.
- 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
- 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.
- Publikační typ
- časopisecké články 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.
- 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
Fanconiho anémie je vzácné autozomálně recesivně dědičné onemocnění, klinicky a geneticky heterogenní, charakterizováno typickými klinickými projevy: malý vzrůst, mikrocefalie, skeletální anomálie, abnormální kožní pigmentace, opoždění vývoje, vrozené srdeční vady, vrozené vady ledvin a jiné. V první dekádě života se manifestuje pancytopenií, která vede k selhání kostní dřeně. Pacienti s Fanconiho anémií mají zvýšené riziko hematologických malignit a solidních tumorů. Diagnóza Fanconiho anémie je založena na cytogenetickém vyšetření, které prokazuje zvýšený výskyt spontánních chromozomálních aberací, jejichž počet stoupá po působení diepoxybutanu nebo mitomycinu C. Fanconiho anémie je heterogenní onemocnění, dosud je popsáno 15 komplementačních skupin, každá z nich je způsobena mutacemi některého z 15 kauzálních genů. Pro komplementační skupinu D1 (FANCD1) není typickým projevem, na rozdíl od ostatních skupin, selhávání kostní dřeně, ale časně se manifestující leukemie a specifické solidní tumory, nejčastěji meduloblastom a Wilmsův tumor ledvin.
Fanconi anemia is a rare autosomal recessive disorder, clinically and genetically heterogeneous, characterized by typical clinical features, such as short stature, microcephaly, skeletal abnormalities, abnormal skin pigmentations, developmental delay and congenital heart, kidney anomalies etc. Pancytopenia leading to bone marrow failure occurs in the first decade. Patients with Fanconi anemia have a high risk of hematologic malignancies and solid tumors. The diagnosis of Fanconi anemia is based on cytogenetic testing for increased rates of spontaneous chromosomal breakage and increased sensitivity to diepoxybutane or mitomycin C. Fanconi anemia is a heterogeneous disorder, at least 15 complementation groups are described, and 15 genes in which mutations are responsible for all of the 15 Fanconi anemia complementation groups have been identified. Unlike other Fanconi anemia complementation groups, for complementation group D1 (FANCD1), the bone marrow failure is not a typical feature, but early-onset leukemia and specific solid tumors, most often medulloblastoma and Wilms tumor, are typical for this complementation group. Key words: Fanconi anemia – complementation group – FANCD1 – BRCA2 gene– leukemia – Wilms tumor – medulloblastoma This work was supported by grant from Norway NF-CZ11-PDP-3-003-2014, MH ČR – RVO, UH Motol 00064203 and OPPK – CZ-2.16./3.1.00/24022. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 14. 7. 2015 Accepted: 6. 12. 2015
- Klíčová slova
- komplementační skupina, FANCD1,
- MeSH
- alely MeSH
- chromozomální aberace MeSH
- cytogenetické vyšetření MeSH
- dvojčata MeSH
- Fanconiho anemie * diagnóza genetika MeSH
- genetické testování MeSH
- geny BRCA2 * MeSH
- leukemie komplikace MeSH
- lidé MeSH
- meduloblastom * etiologie genetika terapie MeSH
- mutace MeSH
- nádory ledvin etiologie genetika MeSH
- nádory mozečku etiologie genetika terapie MeSH
- předškolní dítě MeSH
- rodokmen MeSH
- sourozenci MeSH
- Wilmsův nádor * etiologie genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem 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.
- 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
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.
- 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
- Publikační typ
- abstrakt z konference 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.
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
- Publikační typ
- abstrakt z konference MeSH
