Review

Authors: Angela Peron, Ilaria Catusi, Maria Paola Recalcati...

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issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies.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

Review

Authors: Robert D Daber, Laura K Conlin, Laura D Leonard...

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

Review

Authors: Bruna Burssed, Malú Zamariolli, Fernanda Teixeira Bellucco...

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

Review

Authors: Sylvia A Koza, Anne C Tabet, Maria C Bonaglia...

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

Authors: Sun Young Kim, Elizabeth Wohler, Maria Jimena Gutierrez...

Ring chromosome 17 and 17p13.3 deletion syndrome are phenotypically heterogeneous diseases with similar clinical features. The ring chromosome 17 phenotypic features range from the Miller-Dieker syndrome characterized by deletion of the PAFAH1B1 gene, lissencephaly, hypotonia, dysphagia, café au lait spots, and severe intellectual disability, to a milder phenotype characterized by microcephaly, seizures, delayed development, minor facial dysmorphic features, clinodactyly, short stature, café au lait spots, retinal flecking, and deletion of the YWHAE and CRK genes. Similarly, the phenotypic features of the 17p13.3 deletion syndrome range from the Miller-Dieker syndrome caused by loss of function of the PAFAH1B1 gene and characterized by lissencephaly, microcephaly, seizures, hypotonia, and severe intellectual disability to a milder phenotype characterized by nonspecific white matter changes, microcephaly, seizures, delayed development, short stature, and deletion of the YWHAE and CRK genes. Café au lait spots and retinal or axillary freckling have been noted in the ring chromosome 17 syndrome but not in 17p13.3 deletion syndrome. We report a 5-year-old girl with a history of intrauterine growth retardation, short stature, intractable epilepsy, expressive language disorder, clinodactyly, multiple café au lait spots, and retinal freckling who was initially diagnosed with 17p13.3 deletion syndrome involving YWHAE and CRK but not PAFAH1B1 on CGH array. However, cytogenetic analysis of G-banded chromosomes revealed mosaic ring chromosome 17. Optical genome mapping simultaneously identified the 17p13.3 deletion and the mosaic ring chromosome 17. This case report highlights the limitations of the arrays and sequencing methods for identifying structural variants, the need to investigate further deletions and duplications identified by arrays, mainly considering atypical phenotypic features, and suggests that OGM could be used as a first-tier test with exome sequencing for the diagnosis of patients with dysmorphic features, intellectual disability, and seizure disorder.

Topics: Humans; Chromosomes, Human, Pair 17; Ring Chromosomes; Classical Lissencephalies and Subcortical Band Heterotopias; Phenotype; Female; Chromosome Deletion; Child, Preschool; Intellectual Disability; Microtubule-Associated Proteins; 1-Alkyl-2-acetylglycerophosphocholine Esterase

PubMed: 39513527
DOI: 10.1002/ajmg.a.63925

Authors: Yulia Mostovoy, Philip M Boone, Yongqing Huang...

Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.

Topics: Translocation, Genetic; Humans; Telomere; Ring Chromosomes; Genomic Structural Variation; Chromosome Mapping; Sequence Analysis, DNA; High-Throughput Nucleotide Sequencing

PubMed: 39520989
DOI: 10.1016/j.ajhg.2024.10.006

Review

Authors: César Paz-Y-Miño, Jaime Guevara-Aguirre, Ariane Paz-Y-Miño...

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

Authors: Juan Wang, Ze-Xiong Xie, Yuan Ma...

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

Review

Human ring chromosome registry for cases in the Chinese population: re-emphasizing Cytogenomic and clinical heterogeneity and reviewing diagnostic and treatment strategies.

Authors: Qiping Hu, Hongyan Chai, Wei Shu...

BACKGROUND

Constitutional ring chromosomes are rare orphan chromosomal disorders. Ring chromosome syndrome featuring growth retardation and mild to intermediate intellectual disability is likely caused by the dynamic behavior of ring chromosome through cell cycles. Chromosomal and regional specific phenotypes likely result from segmental losses and gains during the ring formation. Although recent applications of genomic copy number and sequencing analyses revealed various ring chromosome structures from an increasing number of case studies, there was no organized effort for compilating and curating cytogenomic and clinical finding for ring chromosomes.

METHODS

A web-based interactive 'Human Ring Chromosome Registry' using Microsoft Access based relational database was developed to present genetic and phenotypic findings of ring chromosome cases. Chinese ring chromosome cases reported in the literature was reviewed and compiled as a testing data set to validate this registry.

RESULTS

A total of 113 cases of ring chromosomes were retrieved in all chromosomes except for chromosomes 16, 17 and 19. The most frequently seen ring chromosomes by a decreasing order of relative frequencies were ring 13 (14%), X (12%), 22 (10%), 15 (9%), 14 (7%), and 18 (7%). Genomic imbalances were detected in 18 out of 19 cases analyzed by microarray or sequencing. Variable clinical manifestations of developmental delay, dysmorphic facial features, intellectual disability, microcephaly, and hypotonia were noted in most autosomal rings. Chromosomal specific syndromic phenotypes included Wolf-Hirschhorn syndrome in a ring chromosome 4, cri-du-chat syndrome in a ring chromosome 5, epilepsy in ring chromosomes 14 and 20, Turner syndrome in ring chromosome X, and infertility in ring chromosomes 13, 21, 22 and Y. Effective growth hormone supplemental treatment for growth retardation in a ring chromosome 18 was noted.

CONCLUSIONS

Based on findings from these Chinese ring chromosome cases, guidelines for cytogenomic diagnosis and criteria for case registration were proposed. Further research to define underlying mechanisms of ring chromosome formation and dynamic mosaicism, to delineate the genotype-phenotype correlations, and to develop chromosome therapy for ring chromosomes were discussed.

PubMed: 29492108
DOI: 10.1186/s13039-018-0367-3

Authors: Elif Ozsu, Gül Yeşiltepe Mutlu, Belkıs Ipekçi...

Ambiguous genitalia, known to be associated with sex chromosome disorders, may also be seen with autosomal chromosome anomalies. Herein, we report a case with ambiguous genitalia and ring chromosome 13. Ring chromosome 13 is a rare genetic anomaly in which the loss of genetic material determines the clinical spectrum.

Topics: Abnormalities, Multiple; Chromosomes, Human, Pair 13; Disorders of Sex Development; Humans; Infant; Male; Ring Chromosomes

PubMed: 24932608
DOI: 10.4274/Jcrpe.1194