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Molecular Cytogenetics Jun 2022Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic... (Review)
Review
Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic instability. Most of these rearrangements arise from recombination, repair, or replication mechanisms that occur after a double-strand break or the stalling/breakage of a replication fork. Here, we review the mechanisms of formation of structural rearrangements, highlighting their main features and differences. The most important mechanisms of constitutional chromosomal alterations are discussed, including Non-Allelic Homologous Recombination (NAHR), Non-Homologous End-Joining (NHEJ), Fork Stalling and Template Switching (FoSTeS), and Microhomology-Mediated Break-Induced Replication (MMBIR). Their involvement in chromoanagenesis and in the formation of complex chromosomal rearrangements, inverted duplications associated with terminal deletions, and ring chromosomes is also outlined. We reinforce the importance of high-resolution analysis to determine the DNA sequence at, and near, their breakpoints in order to infer the mechanisms of formation of structural rearrangements and to reveal how cells respond to DNA damage and repair broken ends.
PubMed: 35701783
DOI: 10.1186/s13039-022-00600-6 -
European Journal of Medical Genetics May 2012Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to... (Review)
Review
Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.
Topics: Brain Waves; Chromosomes, Human, Pair 20; Humans; Mosaicism; Phenotype; Ring Chromosomes; Seizures; Sequence Deletion; Syndrome
PubMed: 22406087
DOI: 10.1016/j.ejmg.2012.02.004 -
Frontiers in Neurology 2020Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in... (Review)
Review
Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis-especially in the genomic era-and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.
PubMed: 33363513
DOI: 10.3389/fneur.2020.613035 -
Cytogenetic and Genome Research 2013In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in... (Review)
Review
In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in fishes ranges from 2 to 25 kb and shortens with age in some of the species. To date, chromosomal distribution of the telomeric DNA sequences has been examined in approximately 80 fish species of which about 42% show additional telomeric hybridization signals far from the chromosomal termini. Based on the chromosomal location, such internally located telomeric repeats may be classified into 4 categories: (1) telomeric DNA sequences located at the pericentromeric regions, (2) interstitial telomeric sites observed between centromeres and the bona fide telomeres, (3) telomeric DNA sequences that scatter along the nucleolus organizer regions, and (4) telomeric DNA repeats interspersed with the entire chromosomes. Most of the pericentromeric and interstitial telomeric sequences in fish are possible relicts of chromosome fusion events. The origin of the telomeric sequences co- localizing with the major rDNA sequences or scattered along the whole chromosomes is not clear. Internally located telomeric repeats are considered as 'hot spots' for recombination and thus may potentially increase the rates of chromosome breaks and rearrangements leading to the various chromosomal polymorphisms in fishes. FISH with telomeric probe applied to metaphase spreads of androgenetic specimens that hatched from eggs exposed to ionizing radiation before insemination enabled the detection of small radiation-induced fragments of maternal chromosomes. Remnants of the irradiated chromosomes were found to be ring chromosomes with the interstitial telomeric signals, telomerless rings, fragments with fused sister chromatids, and linear fragments with telomeres detected at both of their ends. The increasing availability of techniques enabling the study of fish telomeres and telomerase and the easy access to numerous fish species strongly confirm that these animals are promising models in research concerning the role of telomeres and telomerase in vertebrate aging, repair of ionizing radiation-induced DNA double strand breaks, and chromosomal rearrangements.
Topics: Animals; Base Sequence; Chromosomes; DNA Damage; Fishes; Humans; Telomere
PubMed: 23988378
DOI: 10.1159/000354278 -
Nature Communications Sep 2018Structural variations (SVs) exert important functional impacts on biological phenotypic diversity. Here we show a ring synthetic yeast chromosome V (ring_synV) can be...
Structural variations (SVs) exert important functional impacts on biological phenotypic diversity. Here we show a ring synthetic yeast chromosome V (ring_synV) can be used to continuously generate complex genomic variations and improve the production of prodeoxyviolacein (PDV) by applying Synthetic Chromosome Recombination and Modification by LoxP-mediated Evolution (SCRaMbLE) in haploid yeast cells. The SCRaMbLE of ring_synV generates aneuploid yeast strains with increased PDV productivity, and we identify aneuploid chromosome I, III, VI, XII, XIII, and ring_synV. The neochromosome of SCRaMbLEd ring_synV generated more unbalanced forms of variations, including duplication, insertions, and balanced forms of translocations and inversions than its linear form. Furthermore, of the 29 novel SVs detected, 11 prompted the PDV biosynthesis; and the deletion of uncharacterized gene YER182W is related to the improvement of the PDV. Overall, the SCRaMbLEing ring_synV embraces the evolution of the genome by modifying the chromosome number, structure, and organization, identifying targets for phenotypic comprehension.
Topics: Aneuploidy; Chromosomes, Artificial, Yeast; Gene Deletion; Genetic Engineering; Genetic Variation; Genome, Fungal; Genotype; Haploidy; Indoles; Microorganisms, Genetically-Modified; Phenotype; Polymerase Chain Reaction; Saccharomyces cerevisiae
PubMed: 30224715
DOI: 10.1038/s41467-018-06216-y -
Translational Pediatrics Apr 2015Ring chromosomes arise following breakage and rejoining in both chromosome arms. They are heterogeneous with variable size and genetic content and can originate from any... (Review)
Review
Ring chromosomes arise following breakage and rejoining in both chromosome arms. They are heterogeneous with variable size and genetic content and can originate from any chromosome. Phenotypes associated with ring chromosomes are highly variable as apart from any deletion caused by ring formation, imbalances from ring instability can also occur. Of interest is ring chromosome 20 which has a significant association with epilepsy with seizure onset in early childhood. Severe growth deficiency without major malformations is a common finding in the ring chromosome carrier. This phenotype associated with ring behaviour and mitotic instability and independent of the chromosome involved has been termed the "ring syndrome". Precise genotype-phenotype correlations for ring chromosomes may not be possible as influencing factors vary depending on the extent of deletion in ring formation, ring instability and the level of mosaicism. Although ring chromosomes usually arise as de novo events, familial transmission of rings from carrier to offspring has been described and prenatal diagnosis for any pregnancies should always be considered.
PubMed: 26835370
DOI: 10.3978/j.issn.2224-4336.2015.03.04 -
Seizure Nov 2015To analyze the various types of epilepsy in subjects with chromosome 18 aberrations in order to define epilepsy and its main clinical, electroclinical and prognostic... (Review)
Review
PURPOSE
To analyze the various types of epilepsy in subjects with chromosome 18 aberrations in order to define epilepsy and its main clinical, electroclinical and prognostic aspects in chromosome 18 anomalies.
METHODS
A careful overview of recent works concerning chromosome 18 aberrations and epilepsy has been carried out considering the major groups of chromosomal 18 aberrations, identified using MEDLINE and EMBASE database from 1980 to 2015.
RESULTS
Epilepsy seems to be particularly frequent in patients with trisomy or duplication of chromosome 18 with a prevalence of up to 65%. Approximately, over half of the patients develop epilepsy during the first year of life. Epilepsy can be focal or generalized; infantile spasms have also been reported. Brain imagines showed anatomical abnormalities in 38% of patients. Some antiepileptic drugs as valproic acid and carbamazepine were useful for treating seizures although a large majority of patients need polytherapy.
CONCLUSION
Children with chromosomal 18 abnormalities can present different types of epilepsy, more frequently focal seizures in individuals with 18q- deletion syndrome, while both complex partial seizures and generalized tonic-clonic seizures have been described in patients who suffer for trisomy 18. Outcome in term of seizures frequency and duration seems to be variable and epilepsy is drug resistant in half of the children, especially in children with trisomy 18 and generalized epilepsy.
Topics: Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 18; Epilepsy; Humans; Ring Chromosomes; Translocation, Genetic; Trisomy; Trisomy 18 Syndrome
PubMed: 26552569
DOI: 10.1016/j.seizure.2015.09.013 -
Journal of Medical Case Reports Nov 2018Ring chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and... (Review)
Review
BACKGROUND
Ring chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and mental and motor problems among others. Only 97 clinical cases of ring chromosome 15 syndrome have been reported since 1966 and a common phenotype for these patients has not been established.
CASE PRESENTATION
The present case report describes a 15-month-old girl from the Amazon region of Ecuador, of Mestizo ancestry, who after cytogenetic tests showed a 46,XX,r(15) karyotype in more than 70% of metaphases observed. Her parents were healthy and non-related. The pregnancy was complicated and was positive for intrauterine growth retardation. Her birth weight was 1950 g, her length was 43.5 cm, and she had a head circumference of 29.3. In addition to postnatal growth delay, she had scant frontal hair, small eyes, hypertelorism, low-set of ears, flattened nasal bridge, anteverted nostrils, down-turned mouth, three café au lait spots, and delayed dentition.
CONCLUSIONS
Despite the frequency of some phenotypes expressed in the different clinical cases reviewed and the present case, a common phenotype for patients with ring 15 could not be determined and it is restricted to the region of the chromosome lost during the ring formation.
Topics: Abnormalities, Multiple; Chromosome Aberrations; Chromosome Mapping; Chromosomes, Human, Pair 15; Cytogenetics; Female; Growth Disorders; Humans; Infant; Karyotyping; Phenotype; Ring Chromosomes; Syndrome
PubMed: 30442194
DOI: 10.1186/s13256-018-1879-5 -
Biomolecules Feb 2023The regulation of telomere length has a significant impact on cancer risk and aging in humans. Circular chromosomes are found in humans and are often unstable during... (Review)
Review
The regulation of telomere length has a significant impact on cancer risk and aging in humans. Circular chromosomes are found in humans and are often unstable during mitosis, resulting in genome instability. Some types of cancer have a high frequency of a circular chromosome. Fission yeast is a good model for studying the formation and stability of circular chromosomes as deletion of (encoding a telomere protection protein) results in rapid telomere degradation and chromosome fusion. Pot1 binds to single-stranded telomere DNA and is conserved from fission yeast to humans. Loss of leads to viable strains in which all three fission yeast chromosomes become circular. In this review, I will introduce genetic interactions as these inform on processes such as the degradation of uncapped telomeres, chromosome fusion, and maintenance of circular chromosomes. Therefore, exploring genes that genetically interact with contributes to finding new genes and/or new functions of genes related to the maintenance of telomeres and/or circular chromosomes.
Topics: Humans; Schizosaccharomyces; Shelterin Complex; Schizosaccharomyces pombe Proteins; Telomere-Binding Proteins; Chromosomes, Fungal; Telomere
PubMed: 36830739
DOI: 10.3390/biom13020370 -
European Journal of Medical Genetics Jul 2023This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in... (Review)
Review
This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in SHANK3. It is one of a series of papers written by the European PMS consortium as a consensus guideline. We reviewed the available literature based on pre-set questions to formulate recommendations on counselling, diagnostic work-up and surveillance for tumours related to ring chromosome 22. All recommendations were approved by the consortium, which consists of professionals and patient representatives, using a voting procedure. PMS can only rarely be diagnosed based solely on clinical features and requires confirmation via genetic testing. In most cases, the family will be referred to a clinical geneticist for counselling after the genetic diagnosis has been made. Family members will be investigated and, if indicated, the chance of recurrence discussed with them. Most individuals with PMS have a de novo deletion or a pathogenic variant of SHANK3. The 22q13.3 deletion can be a simple deletion, a ring chromosome 22, or the result of a parental balanced chromosomal anomaly, influencing the risk of recurrence. Individuals with a ring chromosome 22 have an increased risk of NF2-related schwannomatosis (formerly neurofibromatosis type 2) and atypical teratoid rhabdoid tumours, which are associated with the tumour-suppressor genes NF2 and SMARCB1, respectively, and both genes are located on chromosome 22. The prevalence of PMS due to a ring chromosome 22 is estimated to be 10-20%. The risk of developing a tumour in an individual with a ring chromosome 22 can be calculated as 2-4%. However, those individuals who do develop tumours often have multiple. We recommend referring all individuals with PMS and their parents to a clinical geneticist or a comparably experienced medical specialist for genetic counselling, further genetic testing, follow-up and discussion of prenatal diagnostic testing in subsequent pregnancies. We also recommend karyotyping to diagnose or exclude a ring chromosome 22 in individuals with a deletion 22q13.3 detected by molecular tests. If a ring chromosome 22 is found, we recommend discussing personalised follow-up for NF2-related tumours and specifically cerebral imaging between the age of 14 and 16 years.
Topics: Adolescent; Female; Humans; Pregnancy; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 22; Counseling; Neurofibromatosis 2; Ring Chromosomes
PubMed: 37120077
DOI: 10.1016/j.ejmg.2023.104773