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Cytogenetic analysis. G-banding karyotype from a peripheral blood metaphase of the patient: 46,XX,r(6).
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Background
Ring chromosome 6 is a rare constitutional abnormality that generally occurs de novo. The related phenotype may be highly variable ranging from an almost normal phenotype to severe malformations and mental retardation. These features are mainly present when genetic material at the end of the chromosome is lost. The severity of the phenot...
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Context 1
... dicentric ring was found, and the size of the ring appeared to be always the same. No cells were found with two normal chromosomes 6 (Figure 1). Preliminary FISH experiment using the WCP for chro- mosome 6 was performed to distinguish it from other chromosomes and showed both of them entirely painted. ...Similar publications
Côté et al. [1981] suggested that ring chromosomes with or without deletions share a common pattern of phenotypic anomalies, regardless of which chromosome is involved. The phenotype of this 'general ring syndrome' consists of growth failure without malformations, few or no minor anomalies, and mild to moderate mental retardation. We reconsidered t...
Citations
... For two individuals, their terminal deletion was known to be the result of a ring chromosome 6 [23,32]. The ring also included a small terminal 6p deletion without phenotypic consequences [38]. ...
Background
Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals.
Results
Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1 . Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics.
Conclusions
Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.
... defects related to ocular, ear and heart malformations with telorism, intellectual disability and short neck. [4] Ring chromosome 6 was first described in 1973 by Moore et al in a female infant presented with dysmorphic features. Complete rings without any loss of genetic material have been reported in individuals with normal phenotype. [5] As per Ciocca et. al, 2013, patients with ring 6 chromosome exhibit the clinical features that include failure to thrive, congenital heart defects, intellectual disabilities, microcephaly and facial dysmorphism, vision, auditory and central nervous system disorders. However we did not find any eye, ear and heart related abnormalities in the proband which is proba ...
... However we did not find any eye, ear and heart related abnormalities in the proband which is probably due to the clinical variability seen in ring 6 chromosome. [6] Venkateshwari et al. Romke et al, 1987, has mentioned that the individuals having the same breakpoints may also differ with the phenotypical outcomes. ...
... Here, the ring formed in 6p25.3q27 and featured both a distal 6p deletion and a distal 6q duplication. Ciocca et al. (9) reported a newborn girl with a large patent ductus arteriosus (PDA) and secundum ASD. In that patient, the breakpoints were at p25 and q27, similar to our case. ...
... Moreover, a study [37] has reported a 'de novo' missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene in 1/14 (7.1%) patient with periventricular nodular heterotopia, developmental delay and epilepsy through whole exome sequencing. In addition, the authors silenced C6orf70 and two additional genes (phf10 and Dll1) in the developing rat neocortex and suggested that C6orf70 plays a major role Single cell line (one of the chromosome #6 has been replaced by a ring chromosome 6) Publications Pace et al. [13] Ciocca et al. [14] Ahzad et al. [15] Walker et al. [16] Kini et al. [17] Fried et al. [18] Zhang et al. [ Lee et al. [8] Andrieux et al. [21] Kara et al. [22] Nishigaki et al. [23] Hockner et al. [24] Nishi et al. [ Umbilical hernia in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular heterotropia. Developmental delay, intellectual disability, dysmorphism, seizures, dimpling of elbows and knees are some of the main features noted in such patients. ...
Background:
Ring chromosome 6 (r(6)) is a rare disorder that mainly occurs as a 'de novo' event. Nonetheless, a wide phenotypic spectrum has been reported in r(6) cases, depending on breakpoints, size of involved region, copy number alterations and mosaicism of cells with r(6) and/or monosomy 6 due to loss of r(6).
Case presentation:
An 11-year-old male was referred with developmental delay, intellectual disability and microcephaly. Physical examination revealed additionally short stature and multiple facial dysmorphisms. Banding cytogenetic studies revealed a karyotype of mos 46,XY,r(6)(p25.3q27)[54]/45,XY,-6[13]/46,XY,r(6)(::p25.3→q27::p25.3→q27::)[13]/46,XY[6]/47,XY,r(6)(p25.3q27)×2[2]dn. Additionally, molecular karyotyping and molecular cytogenetics confirmed the breakpoints and characterized a 1.3 Mb contiguous duplication at 6p25.3.
Conclusion:
The present study has accurately identified copy number alterations caused by ring chromosome formation. A review of the literature suggests that hemizygous expression of TBP gene in 6q27~qter, is likely to be the underlying cause of the phenotype. The phenotypic correlation and clinical severity in r(6) cases continue to remain widely diverse in spite of numerous reports of genomic variations.
... and present patient). Contrarily, in patients whose 6p25 deletion does not disrupt FOXC1, the phenotype is mild 1 or moderate, 4,8 and does not include ASD.1,4,8,9 Thus, early reports of patients with a severe r(6) phenotype including clear manifestations of ASD are highly indicative of a FOXC1 deletion, in spite of having an apparently discordant cytogenetic breakpoints on 6p(Table S4). ...
... Additionally, FOXC1, FOXC2, FOXF2 and FOXQ1 genes have been associated with cardiovascular anomalies.Moreover, FOXC1, FOXF2, FOXQ1, and GMDS genes are associated with ID and CNS malformations -GMDS was also haploinsufficient in our patient. FOXC1 and SERPINB6 genes are associated with hearing deficits; and FOXF2 with teeth agenesis.3,5,7,9 ...
Here, we report a patient with ring chromosome 6 [r(6)], associated with anterior segment dysgenesis (ASD) and other anomalies. The phenotype was due to a 1,880 kb microdeletion at 6p25.3 identified by whole‐genome array analysis, and was mainly attributable to a FOXC1 haploinsufficiency. Currently 37 patients with r(6) have been reported. We found that facial dysmorphism, ASD, heart anomalies, brain anomalies, and hearing loss are constant features only in severe cases of r(6), mainly related to hemizygosity of FOXC1. Thus, overlaps with other FOXC1 related phenotypes, such as the 6p25 deletion syndrome, Axenfeld‐Rieger syndrome type 3, and ASD type 3. Contrarily, those patients whose r(6) does not disrupt FOXC1, have mild or moderate phenotypes and do not exhibit ASD.
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... Peeden et al reviewed the variability of phenotypic features in 14 cases of ring chromosome 6 [3]. The most frequent clinical features include failure to thrive, congenital heart defects, intellectual disability, microcephaly and facial dysmorphology [4]. Also reported are various abnormalities in the ocular, auditory and central nervous systems. ...
... At least two case reports have described a r(6) involving a comparable deletion at 6p25.3 [4,5]. Both patients had psychomotor delay, cerebral ventriculomegaly, a prominent forehead and malformed ears. ...
Background
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. Case presentationIn 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. Conclusion
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.
... C6orf70 is expressed in developing human brain and is involved in neuronal migration. However, in the previous reports of ring chromosome 6 with 6q27 deletions including C6orf70, periventricular heterotopia has not been pointed out [5,14]. ...
Ring chromosome 6 is a rare chromosome abnormality that arises typically de novo. The phenotypes can be highly variable, ranging from almost normal to severe malformations and neurological defects. We report a case of a 3-year-old girl with mosaic ring chromosome 6 who presented with being small for gestational age and intellectual disability, and whose brain MRI later revealed periventricular heterotopia and white matter abnormalities. Mosaicism was identified in peripheral blood cells examined by standard G-bands, mos 46,XX,r(6)(p25q27)[67]/45,XX,-6[25]/46,XX,dic r(6:6)(p25q27:p25q27)[6]/47,XX,r(6)(p25q27) × 2[2]. Using array-comparative genomic hybridization, we identified terminal deletion of 6q27 (1.5 Mb) and no deletion on 6p. To our knowledge, this is the first report of periventricular heterotopia and white matter abnormalities manifested in a patient with ring chromosome 6. These central nervous system malformations are further discussed in relation to molecular genetics.
... Deletions at the end of both arms of one allele 6 are often involved in this rare de novo event. The presence of a large amount of euchromatin extending beyond distal 6p12.1 and proximal 6q12 (ring chromosome) has been associated with an abnormal phenotype on a girl 46,XX,r(6)(p25q27) (Ciocca et al. 2013). ...
Introduction:
Multiple environmental and genetic factors are involved with the development of basal cell carcinomas (BCC), as well as with breast cancers. Tumor initiation and progression are often associated with genomic instability such as aneuploidies, and gains or losses of large chromosomal segments, known as copy number alterations (CNAs). CNAs have been successfully detected using the microarray comparative genomic hybridization technique (array-CGH) at high resolution. Data thus obtained are useful to identify specific genomic aberrations, to classify tumor stages, and to stratify subgroups of patients with different prognosis and clinical behaviors.
Case description:
Clinical study of a 66-year-old white female identified two primary tumors, a ductal invasive grade-II carcinoma of the breast, and one nodular BCC. Germline and tumor genomic survey utilized the 180 K array-CGH analysis to investigate chromosomal alterations.
Discussion and evaluation:
Several chromosomal anomalies were detected in the breast tumor genome, including focal ~422 Kb 13q13.3 microdeletion. In the BCC, amplification of a chromosome 6 spanning the centromere region between the cytobands 6p23 and 6q12 was identified. Several 6p amplified genes correspond to families of histone and human leukocyte antigen genes, whereas some of the CNAs found in the breast tumor are uncommon. No germline CNA was detected in the normal skin of the patient at this technical resolution.
Conclusion:
CNAs found in the two different tumors of the patient constitute independent events arisen in the somatic lineage. Relevant genes to both carcinogenesis and progression are to be affected by these CNAs.
Ring chromosome 6 (RC6) is a rare constitutional structural abnormality that generally occurs during meiosis or early post-zygotic mitosis. Most of RC6 cases occur de novo except for very rare cases having parental origin. Its preponderance is seen more in males compared to females with majority of RC6 cases identified postnatally with short stature, gross developmental delay, and variable dysmorphic features, whereas prenatal cases are often presented with intra-uterine growth retardation (IUGR) and hydrocephalus. RC6 can be identified primarily by conventional karyotype analysis followed by chromosome microarray analysis (CMA) or next-generation sequencing (NGS) to precisely identify the break points and genomic imbalances. Further identification of candidate genes within the genomic imbalances provides evidence for genotype–phenotype correlations that can be contributory to the variable degree of clinical features. Commonly observed short stature and microcephaly probably represent ‘ring syndrome’ phenotype due to dynamic somatic mosaicism; however, variable penetrance and expressivity caused by genomic imbalance for other clinical features are observed. Banding cytogenetics to define the ring structure and dynamic mosaicism followed by CMA and/or NGS to define genomic imbalances should be performed for patients with RC6, with the goals of exact breakpoint characterization and genotype–phenotype correlations.
The aim of the current review is to report a-CGH abnormalities identified in fetuses with prenatally diagnosed fetal malformations in whom a normal karyotype was diagnosed with conventional cytoge- netic analysis.
A systematic electronic search of databases (PubMed/Medline, EMBASE/SCOPUS) has been conducted from inception to May, 2017. Bibliographic analysis has been performed according to PRISMA statement for review. The following keywords were used: ‘array-CGH’ and ‘fetal malformations” and “prenatal diagnosis”; alternatively, “microarray”, “oligonucleotide array”, “molecular biology”, “antenatal di- agnostics”, “fetal diagnostics”, “congenital malformations” and “ultrasound” were used to capture both “a-CGH” and “prenatal”.
One-hundred and twelve fetuses with prenatally diagnosed fetal malformations with normal kar- yotyping and a-CGH abnormalities detected are described. Single or multiple microarray abnormalities diagnosed have been classified in relation to different organ/system affected. The most frequent a-CGH abnormalities were detected in cases of congenital heart diseases (CDHs), multiple malformations and central nervous system (CNS) malformations. Maternal or paternal carrier-state was seen in 19.64% (22/ 112), of cases while the number of reported de novo mutations accounted for 46.42% (52/112) of all CNVs microarray abnormalities. Array-comparative genomic hydridization (a-CGH) may become an integral and complemantary genetic testing when fetal malformations are detected prenatally in fetuses with normal cytogenetic karyotype. In addition, a-CGH enables the identification of CNVs and VOUS and improves the calculation of recurrent risk and the genetic counseling.
