Ring chromosome 9 in a girl with developmental delay and dysmorphic features: Case report and review of the literature

Sibbesen, Else la Cour; Jespersgaard, Cathrine; Alosi, Daniela; Bisgaard, Anne‐Marie; Tümer, Zeynep

doi:10.1002/ajmg.a.35901

Cited by 11 publications

(4 citation statements)

References 31 publications

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“…The infectious complications, which candidate genes could be CD274 and IL33 at 9p24.1, were seen in the r(9) patient of Qin et al (2016). The four patients with deletion of 9q involving the EHMT1 gene showed features of 9q34.3 deletion syndrome (La Cour Sibbesen et al, 2013;Penacho et al, 2014;Lyu et al, 2019, and present patient). Other phenotypic variations could be caused by triple-sensitivity genes from an extra duplication in the r(9) of Marsudi et al (2018) and the present patient.…”

Section: F I G U R E 2 a Diagramsupporting

confidence: 54%

Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9

Chai

Wen

et al. 2020

American J of Med Genetics Pt A

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Constitutional ring chromosome 9, r(9), is a rare chromosomal disorder. Cytogenomic analyses by karyotyping, array comparative genomic hybridization (aCGH) and whole genome sequencing (WGS) were performed in a patient of r(9). Karyotyping detected a mosaic pattern of r(9) and monosomy 9 in 83% and 17% of cells, respectively. aCGH detected subtelomeric deletions of 407 kb at 9p24.3 and 884 kb at 9q34.3 and an interstitial duplication of 5.879 Mb at 9q33.2q34.11. WGS revealed double strand breaks (DSBs) at ends of 9p24.3 and 9q34.3, inverted repeats at ends of subtelomeric and 9q33.2q34.11 regions, and microhomology sequences at the junctions of this r(9). This is the first report of r(9) analyzed by WGS to delineate the mechanism of ring chromosome formation from repairing of subtelomeric DSBs. The loss of telomeres by subtelomeric DSBs triggered inverted repeats induced intra-strand foldback and then microhomology mediated synthesis and ligation, which resulted in the formation of this r(9) with distal deletions and an interstitial duplication. Review of literature found seven patients of r(9) with clinical and cytogenomic findings. These patients and the present patient were registered into the Human Ring Chromosome Registry and a map correlating critical regions and candidate genes with relevant phenotypes was constructed. Variable phenotypes of r(9) patients could be explained by critical regions and genes of DOCK8, DMRT, SMARCA2, CD274, IL33, PTPRD, CER1, FREM1 for 9p deletions, and the EHMT1 gene for 9q34 deletion syndrome. This interactive registry of r(9) could provide information for cytogenomic diagnosis, genetics counseling and clinical management. K E Y W O R D S clinical and cytogenomic findings, double stand breaks repairing, mechanism of ring chromosome formation, ring chromosome 9, whole genome sequencing 1 | INTRODUCTION Constitutional ring chromosomes which can involve any one of the 22 autosomes and sex chromosomes occur in about 1/50,000 newborns (Kosztolányi, 1987). Ring chromosomes arise typically from the breakage and subsequent fusion of both chromosome arms. Based on the integrity of genetic material, there are two types of ring chromosomes. One type is a complete ring resulting from subtelomeric fusion without any significant loss of genetic material, and the other type of incomplete ring shows distal or interstitial deletions and

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Section: F I G U R E 2 a Diagramsupporting

confidence: 54%

Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9

Chai

Wen

et al. 2020

American J of Med Genetics Pt A

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“…We converted a linear synV to a ring by design, a process that could eventually enable more precise modeling of ring chromosome disorders if performed in mammalian cells. Circular "ring" chromosomes have been reported in a wide variety of human genetic disorders, including epilepsy (14,15), intellectual delay (15), various dysmorphic features (16), leukemia (17), and microcephaly (18,19). Further, therapies for genetic disorders based on chromosome circularization have been proposed (20).…”

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confidence: 99%

“Perfect” designer chromosome V and behavior of a ring derivative

Xie

Mitchell

et al. 2017

Science

201

151

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INTRODUCTION The Saccharomyces cerevisiae 2.0 project (Sc2.0) aims to modify the yeast genome with a series of densely spaced designer changes. Both a synthetic yeast chromosome arm (synIXR) and the entirely synthetic chromosome (synIII) function with high fitness in yeast. For designer genome synthesis projects, precise engineering of the physical sequence to match the specified design is important for the systematic evaluation of underlying design principles. Yeast can maintain nuclear chromosomes as rings, occurring by chance at repeated sequences, although the cyclized format is unfavorable in meiosis given the possibility of dicentric chromosome formation from meiotic recombination. Here, we describe the de novo synthesis of synthetic yeast chromosome V (synV) in the “Build-A-Genome China” course, perfectly matching the designer sequence and bearing loxPsym sites, distinguishable watermarks, and all the other features of the synthetic genome. We generated a ring synV derivative with user-specified cyclization coordinates and characterized its performance in mitosis and meiosis. RATIONALE Systematic evaluation of underlying Sc2.0 design principles requires that the final assembled synthetic genome perfectly match the designed sequence. Given the size of yeast chromosomes, synthetic chromosome construction is performed iteratively, and new mutations and unpredictable events may occur during synthesis; even a very small number of unintentional nucleotide changes across the genome could have substantial effects on phenotype. Therefore, precisely matching the physical sequence to the designed sequence is crucial for verification of the design principles in genome synthesis. Ring chromosomes can extend those design principles to provide a model for genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders. RESULTS We chemically synthesized, assembled, and incorporated designer chromosome synV (536,024 base pairs) of S. cerevisiae according to Sc2.0 principles, based on the complete nucleotide sequence of native yeast chromosome V (576,874 base pairs). This work was performed as part of the “Build-A-Genome China” course in Tianjin University. We corrected all mutations found—including duplications, substitutions, and indels—in the initial synV strain by using integrative cotransformation of the precise desired changes and by means of a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)–based method. Altogether, 3331 corrected base pairs were required to match to the designed sequence. We generated a strain that exactly matches all designer sequence changes that displays high fitness under a variety of culture conditions. All corrections were verified with whole-genome sequencing; RNA sequencing revealed only minor changes in gene expression—most notably, decreases in expression of genes relocated near synthetic telomeres as a result of design. We constructed a functional circular synV (ring_synV) derivative in yeast by precisely joining both chromosome ends (telomeres) at specified coordinates. The ring chromosome showed restoration of subtelomeric gene expression levels. The ring_synV strain exhibited fitness comparable with that of the linear synV strain, revealed no change in sporulation frequency, but notably reduced spore viability. In meiosis, heterozygous or homozygous diploid ring_wtV and ring_synV chromosomes behaved similarly, exhibiting substantially higher frequency of the formation of zero-spore tetrads, a type that was not seen in the rod chromosome diploids. Rod synV chromosomes went through meiosis with high spore viability, despite no effort having been made to preserve meiotic competency in the design of synV. CONCLUSION The perfect designer-matched synthetic chromosome V provides strategies to edit sequence variants and correct unpredictable events, such as off-target integration of extra copies of synthetic DNA elsewhere in the genome. We also constructed a ring synthetic chromosome derivative and evaluated its fitness and stability in yeast. Both synV and synVI can be circularized and can power yeast cell growth without affecting fitness when gene content is maintained. These fitness and stability phenotypes of the ring synthetic chromosome in yeast provide a model system with which to probe the mechanism of human ring chromosome disorders. Synthesis, cyclization, and characterization of synV . ( A ) Synthetic chromosome V (synV, 536,024 base pairs) was designed in silico from native chromosome V (wtV, 576,874 base pairs), with extensive genotype modification designed to be phenotypically neutral. ( B ) CRISPR/Cas9 strategy for multiplex repair. ( C ) Colonies of wtV, synV, and ring_synV strains.

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“…Ring chromosome 9 is a rare chromosome disorder, and a review of the literature has revealed that 28 patients have been described to date [Kadotani et al, 1980;Purandare et al, 2005;Sibbesen et al, 2013]. The cardinal features seen in patients with ring 9 include developmental delay, facial dysmorphism, microcephaly, genital abnormalities, cardiac malformations, limb and skeletal anomalies, and infectious complications [Purandare et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

“…Ring chromosomes are rare unbalanced chromosomal abnormalities that occur in about 1 of 50,000 fetuses [Sibbesen et al 2013]. They have been reported for all human chromosomes and are usually associated with intellectual disability and congenital abnormalities [Arnedo et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature

Sivasankaran

Kanakavalli²,

Anuradha³

et al. 2016

Cytogenet Genome Res

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Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY,-9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed.

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Ring chromosome 9 in a girl with developmental delay and dysmorphic features: Case report and review of the literature

Cited by 11 publications

References 31 publications

Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9

Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9

“Perfect” designer chromosome V and behavior of a ring derivative

Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature

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