Showing papers on "Ring chromosome published in 2017"

"Perfect" designer chromosome v and behavior of a ring derivative

Abstract: 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.

The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan

Abstract: Introduction Turner Syndrome is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X chromosome material. The aim of this study was to extend the established karyotype phenotype relationships using data from a large adult cohort. Materials & Methods Karyotypes were available in 656 (78.1%), 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at- risk individuals. With the exception of bone mineral density T- score for which the lower quartile was allocated as at risk. For co-morbidities, initiation of formal treatment was recorded. Results 45,X/46,XX had considerably lower incidences of co-morbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. Conclusions Karyotype may play an important factor against stratifying risk of co-morbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with co-morbidities. This article is protected by copyright. All rights reserved.

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function.

Abstract: Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15) (p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders.

Guideline recommendations for diagnosis and clinical management of Ring14 syndrome - first report of an ad hoc task force

Abstract: Ring chromosome 14 syndrome is a rare chromosomal disorder characterized by early onset refractory epilepsy, intellectual disability, autism spectrum disorder and a number of diverse health issues. The aim of this work is to provide recommendations for the diagnosis and management of persons affected by ring chromosome 14 syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years subjects affected by ring chromosome 14 syndrome. The literature search was performed in 2016. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. Conventional cytogenetics is the primary tool to identify a ring chromosome. Children with a terminal deletion of chromosome 14q ascertained by molecular karyotyping (CGH/SNP array) should be tested secondarily by conventional cytogenetics for the presence of a ring chromosome. Early diagnosis should be pursued in order to provide medical and social assistance by a multidisciplinary team. Clinical investigations, including neurophysiology for epilepsy, should be performed at the diagnosis and within the follow-up. Following the diagnosis, patients and relatives/caregivers should receive regular care for health and social issues. Epilepsy should be treated from the onset with anticonvulsive therapy. Likewise, feeding difficulties should be treated according to need. Nutritional assessment is recommended for all patients and nutritional support for malnourishment can include gastrostomy feeding in selected cases. Presence of autistic traits should be carefully evaluated. Many patients with ring chromosome 14 syndrome are nonverbal and thus maintaining their ability to communicate is always essential; every effort should be made to preserve their autonomy.

Molecular cytogenetic characterisation of a novel de novo ring chromosome 6 involving a terminal 6p deletion and terminal 6q duplication in the different arms of the same chromosome.

Abstract: Ring chromosome 6 is a rare sporadic chromosomal abnormality, associated with extreme variability in clinical phenotypes. Most ring chromosomes are known to have deletions on one or both chromosomal arms. Here, we report an atypical and unique ring chromosome 6 involving both a distal deletion and a distal duplication on the different arms of the same chromosome. In a patient with intellectual disability, short stature, microcephaly, facial dysmorphology, congenital heart defects and renovascular disease, a ring chromosome 6 was characterised using array-CGH and dual-colour FISH. The de-novo ring chromosome 6 involved a 1.8 Mb terminal deletion in the distal short arm and a 2.5 Mb duplication in the distal long arm of the same chromosome 6. This results in monosomy for the region 6pter to 6p25.3 and trisomy for the region 6q27 to 6qter. Analysis of genes in these chromosomal regions suggests that haploinsufficiency for FOXC1 and GMDS genes accounts for the cardiac and neurodevelopmental phenotypes in the proband. The ring chromosome 6 reported here is atypical as it involves a unique duplication of the distal long arm. Furthermore, the presence of renovascular disease is also a unique feature identified in this patient. To the best of our knowledge, a comparable ring chromosome 6 involving both a distal deletion and duplication on different arms has not been previously reported. The renovascular disease identified in this patient may be a direct consequence of the described chromosome rearrangement or a late clinical presentation in r(6) cases. This clinical finding may further support the implicated role of FOXC1 gene in renal pathology.

Disorder of sex development in a cat with chromosome mosaicism 37,X/38,X,r(Y)

Abstract: An 18-month-old European shorthair cat was subjected to genetic studies due to ambiguous external genitalia (underdeveloped both penis and scrotum). Further anatomic and histopathological studies revealed the presence of abdominal, atrophic testes and uterus. Cytogenetic analysis showed two cell lines, one with X monosomy-37,X [90% of the analysed metaphase spreads], and other line had 38 chromosomes with normal X chromosome and abnormally small Y-derived chromosome-38,X,der(Y) [10%]. Further fluorescence in situ hybridization study with telomeric probe revealed a ring structure of the der(Y). Eight Y chromosome-specific genes, SRY, TETY1, TETY2, CUL4BY, CYORF15, HSFY, FLJ36031Y and ZFY, were detected. We conclude that the described abnormality of the reproductive system, leading to sterility, was caused by a very rare type of chromosomal mosaicism-37,X/38,X,r(Y).

Detection of paternal uniparental disomy 9 in a neonate with prenatally detected mosaicism for a small supernumerary marker chromosome 9 and a supernumerary ring chromosome 9.

Abstract: Objective We present the association of paternal uniparental disomy (UPD) 9 with mosaicism for a small supernumerary marker chromosome 9 [sSMC(9)] and a supernumerary ring chromosome 9 [r(9)]. Materials and methods A 38-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+mar [25]/48,XY,+mar,+r(9) [4]/47,XY,+r(9) [1]/46,XY [6]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of cultured amniocytes revealed a result of de novo 9p13.1q21.11 (38,792,472–71,026,063) × 2.64. The marker chromosome was determined to be an sSMC(9) by spectral karyotyping and aCGH. A phenotypically normal baby was delivered at 38 weeks of gestation. During pediatric follow-ups at age two years, the neonate manifested normal psychomotor and growth development. Cytogenetic analysis, metaphase fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) aCGH and polymorphic DNA marker analysis were performed on the peripheral blood of the neonate. Results The neonate's blood had the following results. Metaphase FISH confirmed coexistence of the sSMC(9) and the supernumerary r(9). The karyotype was 47,XY,+sSMC(9) [14]/48,XY, +sSMC(9),+r(9) [10]/47,XY,+r(9) [6]/46,XY [10]. SNP aCGH revealed arr 9p22.3q21.11 (14,234,165–71,035,608) × 2–3, arr 9p24.3p22.3 (216,123–14,629,321)hmz, arr 9p21.3p13.2 (24,769,722–36,732,597)hmz and arr 9q21.11q34.3 (71,013,799–141,011,581)hmz. Polymorphic DNA marker analysis showed paternal isodisomy 9. Conclusion Individuals with mosaicism for sSMC(9) and supernumerary r(9) may be associated with paternal UPD 9.

A novel system for correcting large-scale chromosomal aberrations: ring chromosome correction via reprogramming into induced pluripotent stem cell (iPSC)

Abstract: Approximately 1 in 500 newborns are born with chromosomal abnormalities that include trisomies, translocations, large deletions, and duplications. There is currently no therapeutic approach for correcting such chromosomal aberrations in vivo or in vitro. When we attempted to produce induced pluripotent stem cell (iPSC) models from patient-derived fibroblasts that contained ring chromosomes, we found that the ring chromosomes were eliminated and replaced by duplicated normal copies of chromosomes through a mechanism of uniparental isodisomy (Bershteyn et al. 2014, Nature 507:99). The discovery of this previously unforeseen system for aberrant chromosome correction during reprogramming enables us for the first time to model and understand this process of cell-autonomous correction of ring chromosomes during human patient somatic cell reprograming to iPSCs. This knowledge could lead to a potential therapeutic strategy to correct common large-scale chromosomal aberrations, termed "chromosome therapy".

Continuing role for classical cytogenetics: Case report of a boy with ring syndrome caused by complete ring chromosome 4 and review of literature.

Abstract: Constitutional ring chromosomes can be found for all human chromosomes and are very rare chromosomal abnormalities. A complete ring chromosome without loss of genetic material results from fusion of subtelomeric regions or telomere-telomere fusion. In cases of complete ring chromosome, an increased incidence of severe growth failure with no or only minor anomalies has been observed and attributed to ring syndrome. Ring syndrome is thought to be caused by "dynamic mosaicism" due to ring instability. We report a 6-year-old boy with de novo ring chromosome 4 and typical characteristics of the ring syndrome, namely, proportionate severe growth failure, microcephaly, and minor anomalies. Cytogenetic studies showed complete ring chromosome 4 with mitotic instability. Microarray gave normal results, thus excluding the loss of detectable genetic material. The literature of complete ring chromosome 4 is reviewed. Our case report supports the theory of ring syndrome. No studies about the effects and possible side effects of growth hormone therapy on patients with ring chromosomes have yet been published. We suggest that cytogenetic monitoring of the rate of secondary aberrations in patients with ring chromosome undergoing growth hormone therapy might be feasible. Since the diagnosis would have been missed by molecular karyotyping, our case report underlines the continuing role of classical cytogenetics for the evaluation of structural chromosomal abnormalities in patients with mental and/or physical anomalies. Standard karyotyping is still indispensable and should have an ongoing role as first-tier analysis together with molecular karyotyping. © 2017 Wiley Periodicals, Inc.

RUNX1 amplification in AML with myelodysplasia-related changes and ring 21 chromosomes.

Abstract: Ring 21 is an unstable structural abnormality of chromosome 21 that can lead to RUNX1 gene amplification. We present a unique case with a carrier patient of a constitutional ring chromosome 21 (partial monosomy and trisomy 21) with dysmorphic features and congenital malformations phenotype, who developed acute myeloid leukaemia with myelodysplasia-related changes and two ring 21 chromosomes with RUNX1 amplification. The patient's constitutional ring 21 chromosome showed alterations in tumour suppressor genes, and oncogenes, but not in RUNX1. RUNX1 gene expression at acute myeloid leukaemia diagnosis, showed no upregulation, so other genes may also be the genetic amplification targets in this patient. Copyright © 2016 John Wiley & Sons, Ltd.

Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22.

Abstract: Atypical teratoid rhabdoid tumors of the central nervous system are rare, highly malignant, embryonal tumors most often occurring in children under age 3 years. Most are due to a somatic change in tumor suppressor gene SMARCB1 followed by a second-hit, typically loss of heterozygosity, best detected on immunohistochemical staining. Despite the noteworthy genetic homogeneity of atypical teratoid rhabdoid tumors, relatively little is known about the oncogenic mechanisms that lead to biallelic inactivation of SMARCB1. Herein, we describe a patient with constitutional ring chromosome 22, Phelan-McDermid syndrome and atypical teratoid rhabdoid tumor of the brain. During mitosis, sister chromatids of a ring chromosome may form interlocking and dicentric rings, resulting in chromosomal loss, complex karyotypes, and ongoing somatic variation. We hypothesized that the inherent instability of the patient's ring chromosome could lead to mosaic monosomy chromosome 22, resulting in allelic inactivation of the tumor-suppressor gene SMARCB1 and AT/RT if a second-hit occurred. Utilizing high-density microarray technology to analyze peripheral blood and tumor tissue, we confirmed this oncogenic mechanism, previously undescribed in patients with atypical teratoid rhabdoid tumors. Our data demonstrate chromosomal loss as a consequence of ring chromosome instability serving as the first hit in oncogenesis. This rare but possibly under-recognized mechanism is important to note in children with ATRT and syndromic features. Further investigation is warranted to assess if this oncogenic mechanism has management and/or prognostic implications. © 2016 Wiley Periodicals, Inc.

Molecular characterization and evaluation of complex rearrangements in a case of ring chromosome 15

Abstract: Ring chromosome 15 is a rare genetic entity. Only a few cases have been reported with characterization using molecular techniques. The clinical presentation is quite variable, as a result of differences in the breakpoints, haploinsufficiency of genes involved in deleted segment/s, level of mosaicism and ring instability resulting in a variability of rearrangement of genetic material. The proband, a 2 months old boy, presented with small head size and facial dysmorphism. On examination microcephaly, triangular face, small anterior frontanelle, micrognathia, hypotonia, unilateral simian crease, hypertelorism, umbilical hernia, micropenis with mild phimosis were noted. Karyotype revealed 46,XY,r(15)(p11.2q26). Array-comparative genomic hybridization (aCGH) and targeted gene sequencing for microcephaly was carried out for genotype phenotype correlation. Array-CGH detected a 2.8 Mb terminal deletion at 15q26.3 along with a 496 kb interstitial micro-duplication, encompassing the IGF1R gene, in the affected genomic region, which was otherwise missed on conventional karyotype. The present study highlights the importance of aCGH in not only delineating specific phenotypes through accurate genotypic correlation but also in detection and evaluation of ring chromosome with unexpected complex rearrangements.

Molecular and Cytogenetic Characterization of a Fetus with Mosaic Ring Chromosome 13: A Very Rare Case.

Abstract: The major mechanism for ring chromosome formation is thought to result from breakage and reunion at the breakpoints on the long and short arms of a chromosome. This fusion event can produce terminal arm inversions, deletions, and duplications that determine the resulting phenotype.[1] Ring chromosome 13 is relatively uncommon, with an estimated incidence of 1/58,000 live births. Clinical severity of ring chromosome 13 syndrome is broad and influenced by the stability of the ring as well as the extent of the deletions and/or duplications along chromosome 13.[2] Prenatal diagnosis of ring chromosome 13 is very rare. Here, we present a prenatal case with molecular cytogenetic characterization of mosaic ring chromosome 13 syndrome in a fetus with multiple abnormal ultrasound findings.

Low-Level Chromosomal Mosaicism in Neurodevelopmental Disorders.

Abstract: Chromosomal mosaicism, which represents a diagnostic challenge for detection and interpretation, has been described in several genetic conditions. It can contribute to a large phenotypic variation in diseases. At analysis of a well-characterized cohort of 714 patients with neurodevelopmental disorders (NDDs) of unknown etiology using a high-resolution chromosomal microarray platform, we found 2 cases (0.28%) of low-level mosaicism and defined a previously detected extra chromosome in a third patient. Two of the cases were mosaics for segmental imbalances (a partial trisomy 3q26.1q27.3 and a partial monosomy 18q21.2qter with 14.6 and 20% mosaic ratios in lymphocytes, respectively), and 1 was a mosaic for an entire chromosome (trisomy 14, mosaic ratio 20%). Our diagnostic yield is in line with the ratios previously published in patients with intellectual disability. Notably, the partial trisomy 3q26.1q27.3 case is an example of a rare and unusual class of a rearranged neocentric ring chromosome, which can neither be categorized in class I, nor in class II of such rearrangements. Our cases further elucidate the phenotypes related to the aberrations of the specific chromosome segments observed and underline the important role of low-level mosaics in the pathogenesis of NDDs of unknown etiology even in the absence of clinical signs of mosaicism.

Fecundity in an infertile man with r(15) - a challenge to the current paradigm.

Abstract: Ring chromosome 15 [r(15)] is a rare condition with a mild-to-severe growth failure, mental disabilities, cafe-au-lait spots, specific facial features, fertility difficulties and other minor dysmorphic stigmata. Of almost 50 affected individuals reported in the literature, none were assessed for the precise breakpoint positioning, which creates uncertainty in defining a specific phenotype for the deleted segment. This study reports for the first time the vertical transmission of r(15) in three consecutive generations of a family, including a subfertile man, his mother and his newborn infant. Array comparative genomic hybridization results revealed a 563 kb deletion of 15q26.3, overlapping the OMIM genes SNRP1, PCSK6 and TM2D3. The hemizygosity was confirmed with real-time quantitative PCR. Regarding haploinsufficiency in 15q26.3, based on phenotypic characteristics of the carriers, the only rational conclusion is that SNRPA1, PCSK6 and TM2D3 are not gene-dosage sensitive and are probably inherited in an autosomal-recessive manner. Given growth deficiency in r(15) carriers, this shows that the growth retardation cannot be attributed entirely to IGF1R. The predominance of female patients with r(15) is the next as yet unanswered question; incomplete penetrance and/or variable expression of gene(s) in different genders may be involved, but further evidence is needed to support this idea.

Rheumatoid arthritis in an adult patient with mosaic distal 18q-, 18p- and ring chromosome 18

Abstract: Ring chromosome 18 has a highly variable phenotype, depending on the extent of distal arm deletions. It is most commonly presented as a combination of 18p- and distal 18q- syndrome. IgA deficiency and autoimmune diseases have been previously described in these patients. Seven cases of juvenile rheumatoid arthritis (JRA) have been reported. Here we report the first case of late onset rheumatoid arthritis (RA) in a 32 year old Dominican woman with hypothyroidism, vitiligo, IgA deficiency, interstitial lung disease (ILD), cystic bronchiectasis, and features consistent with ringed 18, 18p- and distal 18q syndrome. The multiple autoimmune findings in our patient lends further support to the idea of loci on chromosome 18 playing a role in autoimmune disease expression. Late onset RA and ILD in a patient with chromosome 18 abnormalities are novel findings and are additional conditions to be aware of in this population.

Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum.

Abstract: Ring chromosome 13 is a rare genetic condition with an incidence of 1/58,000 in live births. Major clinical features of patients with ring chromosome 13 include growth and developmental retardation, microcephaly, facial dysmorphism, ambiguous genitalia, anal atresia, eye malformations, retinoblastoma, and hand, foot, and toe abnormalities. The severity of the phenotype depends on the amount of genetic material lost during ring chromosome formation. Here, we report 2 cases with ring chromosome 13 at either end of the phenotypic spectrum.

A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

Abstract: Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc.

A rare cause of temple syndrome.

Abstract: An 11-year-old girl was referred from the regional paediatric department to the clinical genetic clinic for assessment of intellectual disability. She was the second child of a nonconsanguineous Chinese couple, born at 39 weeks’ gestation, with A birth weight of 1.9 kg (< third percentile) through Caesarian section. Antenatally, she had mild intrauterine growth retardation since 32 weeks’ gestation; otherwise, the antenatal course was unremarkable. She had mild perinatal depression during delivery because of cord around neck. Postnatally, she had poor feeding and failure to thrive, and this was regularly followed up at the neonatal clinic. The feeding improved with oromotor training, but weight gain was still poor despite calorie supplementation. Developmental assessment at the age of 5 years using the Wechsler Intelligence Scale for Children – Fourth Edition (Hong Kong, China) WISC-IV(HK) showed that she had limited intelligence. At the age of 6 years, she had premature thelarche. Luteinizing hormone-releasing hormone (LHRH) stimulation test was suggestive of central precocious puberty and she was put on an LHRH analogue until the age of 11 years. MRI brain and ultrasound pelvis was normal. Because of poor growth, she was also receiving growth hormone at a dose of ∼ 1 U/kg/week for 3 years from 8 to 10 years of age, but the response was not satisfactory, with a gain in height of only 5–6 cm/year. The thyroid function and growth hormone provocation test were normal. Physical examination at the genetic clinic at the age of 11 years showed that she had subtle dysmorphic features, namely, short and anteverted nostrils, a depressed nasal bridge and a broad nasal tip (Fig. 1) with relatively small hands and feet (the hand length was 14.5 cm at the third percentile and foot length was 20 cm at < third percentile). Her body height was at the third percentile (midparental height at the 90th percentile), body weight was at the 50rd percentile and head circumference was at the 25th percentile. Her BMI was 24 kg/m. There was scoliosis with a leg-length discrepancy of 1 cm. No facial or body asymmetry was present. There were no skin pigmentary abnormalities. On the basis of the above clinical features, peripheral blood for the G band at the 550 band level was performed. The result was mos 47, XX+ r[7]/46, XX[43]. Microarray confirmed that the ring chromosome was derived from chromosome 14 with arr[hg19] 14q11.2q22.1(20 483 247–52 205 241)× 2–3.

[Detection of a patient with ring chromosome 15 by low-coverage massively parallel copy number variation sequencing].

Abstract: Objective To explore the genetic cause for a child with developmental delay. Methods The karotypes of the child and her parents were analyzed with G-banding analysis. Their genome DNA was analyzed with low-coverage massively parallel copy number variation sequencing (CNV-seq) and verified by single nucleotide polymorphism array (SNP-array). Results The karyotype of the child was ascertained as 46, XX, r(15)(p13q26.3), while both parents showed a normal karyotype. CNV-seq and SNP-array have identified a de novo 15q26.2-q26.3 deletion in the child with a size of approximately 3.60 Mb. Conclusion The abnormal phenotype of the patient carrying the ring chromosome 15 may be attributed to the presence of the 15q26.2-q26.3 microdeletion. The deletion and haploinsufficiency of the IGF1R gene probably underlie the main clinical features of the patient. Key words: Ring chromosome 15; 15q26 microdeletion; Growth retardation; Low-coverage massively parallel copy number variation sequencing; Single nucleotide polymorphism array

Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients

Abstract: Small supernumerary ring chromosome 6 (sSRC[6]) is a rare chromosomal abnormality characterized by a broad clinical phenotype. The spectrum of this disorder can range from phenotypically normal to severe developmental delay and congenital anomalies. We describe two unrelated patients with small SRCs derived from chromosome 6 with a novel bone phenotype. Both patients presented with a complex bone disorder characterized by severe osteopenia, pathologic fractures, and cyst-like lesions within the bone. Imaging revealed decreased bone mineral density, mutiple multiloculated cysts and cortical thinning. Lesion pathology in both patients demonstrated a bland cyst wall with woven dysplastic appearing bone entrapped within it. In patient 1, array comparative genomic hybridization (CGH) detected a tandem duplication of region 6p12.3 to 6q12 per marker chromosome. Cytogenetic analysis further revealed a complex patient of mosaicism with some cell lines displaying either one or two copies of the marker indicative of both tetrasomy and hexasomy of this region. Patient 2 was mosaic for a sSRC that encompassed a 26.8 Mb gain from 6p21.2 to 6q12. We performed an in-depth clinical analysis of a phenotype not previously observed in sSRC(6) patients and discuss the potential influence of genes located within this region on the skeletal presentation observed.

Structural Changes in Chromosomes

Abstract: Chromosomes can be structurally identified by their sizes, positions of centromeres and nucleolar organizers, and patterns of chromomeres, heterochromatin, and bands. There are four types of aberrations in the chromosomal structure such as deletions, duplications, inversions, and translocations which can be detected cytologically under the microscope. Some changes are however too subtle to be detected cytologically. Deletions represent missing segments of chromosomes. The homozygous deletions can be lethal, whereas heterozygous deletions can be nonlethal or lethal and can express recessive genes uncovered by deletion. Duplications can cause an imbalance in the genetic material, thereby producing phenotypic effect in the organism and leading to increased variety of gene functions. Inversions are caused by 180 degree turn of a segment of a chromosome, which cause little problem for an organism under homozygous condition, but inversion heterozygotes often have pairing difficulties during meiosis, leading to formation of inversion loops. Crossing over within loops usually results in inviable products. The crossover products will be different for pericentric and paracentric inversions. Translocations involve relocation of a chromosomal segment to another position in the genome. In heterozygous state, the translocations produce duplication-deletion meiotic products, which can lead to unbalanced zygotes, and new gene linkages. Chromosome rearrangements can cause ill health in human population – infertility and mental retardation being the dominant effects.

Complex Mosaic Ring Chromosome 11 Associated with Hemizygous Loss of 8.6 Mb of 11q24.2qter in Atypical Jacobsen Syndrome

Abstract: Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving terminal chromosome 11q. The haploinsufficiency of multiple genes contributes to the overall clinical phenotype, which can include the variant Paris-Trousseau syndrome, a transient thrombocytopenia related to FLI1 hemizygous deletion. We investigated a boy with features of JBS using classic cytogenetic methods, FISH and high-resolution array CGH. The proband was found to have a mosaic ring chromosome 11 resulting in a hemizygous 11q terminal deletion of 8.6 Mb, leading to a copy number loss of 52 genes. The patient had a hemizygous deletion in the FLI1 gene region without apparent thrombocytopenia, and he developed diabetes mellitus type I, which has not previously been described in the spectrum of disorders associated with JBS. The relationship of some of the genes within the context of the phenotype caused by a partial deletion of 11q has provided insights concerning the developmental anomalies presented in this patient with atypical features of JBS.

An Interstitial 4q Deletion with a Mosaic Complementary Ring Chromosome in a Child with Dysmorphism, Linear Skin Pigmentation, and Hepatomegaly

Abstract: Interstitial deletions of 4q are rarely reported, vary in size, and have limited genotype-phenotype correlations. Here, genome-wide array CGH analysis identified a 21.6 Mb region of copy number loss at 4q12-q21.1 in a patient diagnosed with dysmorphism, linear skin pigmentation, and hepatomegaly. An additional small ring chromosome was detected in 5/30 cells examined via G-banding. Confirmation of the origin of the ring chromosome was obtained by FISH analysis which identified that the ring chromosome contained material from the deleted region of chromosome 4 and was therefore complementary to the 21.6 Mb deletion. Further microarray studies in the proband using a different microarray platform showed no evidence of mosaicism. This case highlights the importance of an integrated approach to cytogenetic analysis and demonstrates the value of G-banding for detecting mosaicism, as current microarray platforms are unable to detect low level mosaics.

Complex karyotype including ring chromosome 11 in a patient with acute myeloid leukemia: case report.

Abstract: Context: Complex karyotypes in acute myeloid leukemia (AML) are characterized by an overall low response rate with frequent relapses after clinical treatment. Case report: Here, we describe the case of a 61-year-old obese female with clinically diagnosed AML who presented a complex karyotype involving an uncommon abnormality: ring chromosome 11. Immunophenotypic analysis confirmed the diagnosis. Classical and molecular cytogenetic analyses, using GTG banding and FISH (fluorescence in situ hybridization), revealed the presence of complex structural rearrangement involving r(11), add(12)(p13), der(5) and der(13). Conclusions: Molecular cytogenetic analysis is suitable for better identification and characterization of chromosomal rearrangements in AML. Case reports like this, as well as population-based studies, are necessary for understanding the karyotypic changes that occur in humans.

Phenotypical heterogeneity of morpheic seizures in ring chromosome 20 syndrome: a videopolysomnographic evidence.

Abstract: Ring chromosome 20 [r(20)] syndrome is characterized by the coexistence of different epileptic seizures: focal seizures, generalized tonic–clonic seizures (GTCS), and non convulsive status epilepticus (NCSE) [1]. Little is known about sleep manifestations in [r(20)] syndrome and only a few studies describe the characteristics of sleep-related seizures in these patients [2]. A lack of description of definite phenotypical features makes difficult any attempt of an early diagnosis. We describe the wide phenotypical heterogeneity of nocturnal seizures in a patient with [r(20)] syndrome. A 35-year-old woman came to our attention for the presence of seizures started from the age of 10. She did not show any dysmorphic feature and her psychomotor development was normal. General and neurological examinations were normal such as her brain magnetic resonance imaging. A cytogenetic study revealed a mosaic pattern with two cell lines, one that was normal (70% of cells) and one with ring chromosome 20 (30% of cells) [46,XX,r(20) (p13 q13)/46,XX]. The patient underwent a videopolysomnography and different types of seizures were recorded during the same night. One type of seizures was characterized by sudden arousals with prolonged confusional state associated with incoherent speech and fluctuating responsiveness. EEG during these events was characterized by continuous generalized spike and slow wave complexes (Fig. 1a). The second type of episodes were represented by focal motor seizures with head and eyes deviation to the left, ipsilateral trunk rotation followed by limbs’ automatisms and clonic movements, lasting for a few minutes (Fig. 1b). Another type of seizure was represented by the patient suddenly sitting on the bed, screaming and moving her arms with a frightened expression (Fig. 1c). Moreover, stereotyped dystonic postures, gestural automatisms, eyelids flickering and ocular exploring movements were recorded. Ictal EEG of the latter episodes showed rhythmic discharges of monomorphic sharp theta activity over the frontal regions. We report the electroclinical features of nocturnal seizures in a patient with [r(20)] syndrome. A wide variety of clinical phenotypes was recorded during the same night: NCSE; seizures of frontal semeiology characterized by head and eyes deviation and clonic movements; events of temporal origin with manifestations of fear; seizures of occipital semeiology characterized by ocular exploring movements; features compatible with a parietal lobe origin such as trunk and arms rotation. To date, there are no videopolysomnographic evidences of the phenotypical heterogeneity of nocturnal seizures in [r(20)] syndrome. The prevalent occurrence of seizures during sleep is a characteristic shared with autosomic dominant nocturnal frontal lobe epilepsy (ADNFLE). It is not surprising that the gene coding for the neuronal nicotinic acetylcholine receptor, subunit A4 (CHRNA4) has been mapped on the distal long arm of chromosome 20 and its mutation or deletion has been identified in ADFNLE [3]. & Mario Zappia m.zappia@unict.it

Ring chromosome 11 with KMT2A (MLL; 11q23) amplification and deletion in a patient with acute myeloid leukemia

Abstract: Background: Chromosome abnormalities are significant in the diagnosis, prognosis, and treatment of patients with hematologic malignancies. Rearrangements of the mixed lineage leukemia gene (KMT2A; i.e. MLL) can