Genomic Chaos (Multiple Copy Number Variations and Structural Reorganization) Detected in Two Prenatal Cases

The use of new technologies in the routine diagnosis of constitutional abnormalities, such as high-resolution chromosomal microarray and next-generation sequencing, has unmasked new mechanisms for generating structural variation of the human genome. For example, complex chromosome rearrangements can originate by a chromosome catastrophe phenomenon in which numerous genomic rearrangements are apparently acquired in a single catastrophic event. This phenomenon is named chromoanagenesis (from the Greek “chromo” for chromosome and “anagenesis” for rebirth). Herein, we report 2 cases of genomic chaos detected at prenatal diagnosis. The terms “chromothripsis” and “chromoanasynthesis” and the challenge of genetic counseling are discussed.

An Apparently Balanced Complex Chromosome Rearrangement Involving Seven Breaks and Four Chromosomes in a Healthy Female and Segregation/Recombination in Her Affected Son

Duplication of the distal 1q and 4p segments are both characterized by the presence of intellectual disability/neurodevelopmental delay and dysmorphisms. Here, we describe a male with a complex chromosome rearrangement (CCR) presenting with overlapping clinical findings between these 2 syndromes. In order to better characterize this CCR, classical karyotyping, FISH, and chromosomal microarray analysis were performed on material from the patient and his parents, which revealed an unbalanced karyotype with duplications at 1q41q43 and 4p15.2p14 in the proband. The rearrangements, which were derived from a maternal balanced karyotype, included an insertion of a segment from the long to the short arm of chromosome 1, a balanced translocation involving chromosomes 14 and 18, and an insertion of a segment from the short arm of chromosome 4 into the derived chromosome 14. This study aimed to better define the clinical history and prognosis of a patient with this rare category of chromosomal aberration. Our results suggest that the frequency of CCR in the general population may be underestimated; when balanced, they may not have a phenotypic effect. Moreover, they emphasize the need for cytogenetic techniques complementary to chromosomal microarray for proper genetic counseling.

Complex Chromosome-Positive Acute Myelogenous Leukemia Identified 16 Months following the Completion of Capecitabine Chemotherapy for Early-Stage Colon Cancer

Capecitabine is an oral chemotherapy that is used to treat several cancer types, including breast, gastrointestinal, hepatobiliary, and ovarian. The use of antimetabolites in cancer therapy has generally not been associated with leukemogenesis. In this report, we demonstrate a case of capecitabine-related acute myeloid leukemia that was diagnosed 16 months after the completion of treatment for early-stage colon cancer, by a complex chromosome analysis 48,XY,6,del(7)(q22),+8,+13,t(13;17)(q12;p13),t(13,21)(q12;122),+mar [Gazi Med J. 2018 Jan;29(1):57–58]. This is the first report to our knowledge of the development of t-AML in a patient with early-stage colon cancer that was caused by capecitabine. We should use capecitabine with caution. Further studies are essential to investigate capecitabine-triggered leukemogenesis.

KCTD19 associates with ZFP541 and HDAC1 and is required for meiotic exit in male mice

Meiosis is a cell division process with complex chromosome events where various molecules must work in tandem. To find meiosis-related genes, we screened evolutionarily conserved and reproductive tract-enriched genes using the CRISPR/Cas9 system and identified potassium channel tetramerization domain containing 19 (Kctd19) as an essential factor for meiosis. In prophase I, Kctd19 deficiency did not affect synapsis or the DNA damage response, and chiasma structures were also observed in metaphase I spermatocytes of Kctd19 KO mice. However, spermatocytes underwent apoptotic elimination during the metaphase-anaphase transition. We were able to rescue the Kctd19 KO phenotype with an epitope-tagged Kctd19 transgene. Immunoprecipitation-mass spectrometry identified zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1) as binding partners of KCTD19, indicating that KCTD19 is involved in chromatin modification. Phenotyping of Zfp541 KO spermatocytes demonstrated XY chromosome asynapsis and recurrent DNA damage in the late pachytene stage, leading to apoptosis. In summary, our study reveals that KCTD19 associates with ZFP541 and HDAC1, and that both KCTD19 and ZFP541 were essential for meiotic exit in male mice.Author summaryMeiosis is a fundamental process that consisting of one round of genomic DNA replication and two rounds of chromosome segregation producing four haploid cells. To properly distribute their genetic material, cells need to undergo complex chromosome events such as a physical linkage of homologous chromosomes (termed synapsis) and meiotic recombination. The molecules involved in these events have not been fully characterized yet, especially in mammals. Using a CRISPR/Cas9-screening system, we identified the potassium channel tetramerization domain containing 19 (Kctd19) as an essential factor for meiosis in male mice. Further, we identified zinc finger protein 541 (ZFP541) and histone deacetylase 1 (HDAC1) as binding partners of KCTD19. By observing meiosis of Zfp541 knockout germ cells, we found that Zfp541 was also essential for meiotic completion. These results show that the KCTD19/ZFP541 complex plays a critical role and is indispensable for male meiosis and fertility.

Clinical and neurological findings of a patient with a complex chromosome 5 alteration

Context: Inversion-duplication-deletion (invdupdel) involving the short arm of chromosome 5 is considered a complex and extremely rare alteration. Case report: A female patient was born prematurely at 32 weeks and was delivered by cesarean section, weighing 2,086 grams, with an Apgar score in the fifth minute of 7. After birth, she needed invasive mechanical ventilation. A nasofibrolaryngoscopy was performed, which revealed the rear projection of the tongue base. The speech-language evaluation showed a swallowing disorder. The patient needed to be tracheostomized and evolved with episodes of cardiorespiratory arrest. A zone 2 of immaturity was identified in both eyes. Then, gastroesophageal reflux was also diagnosed. Cerebral ultrasound showed moderate lateral ventricles dilation. High resolution GTG-banding karyotype identified an inverted and partial duplication of the chromosome’s 5 short arm, with a probable deletion of its distal segment: 46,XX,invdup(5) (p13.3->p15.33:: p15.33->qter) [23]. The parents’ karyotype was normal. At 2 months, the patient had dolichocephaly; bitemporal narrowing; hypertelorism; and down slanting palpebral fissures with blepharophimosis; low-set and posteriorly rotated ears; leftover skin at neck and bilateral plantar creases between the first, second and third toes. Conclusions: Invdupdel of the short arm of chromosome 5 is a very rare chromosomal alteration. Neurological findings seem to be part of its clinical manifestations, especially dilated lateral ventricles. More reports will be essential for understanding its clinical spectrum.

Chromosome dynamics and spatial organization during the non-binary cell cycle of a predatory bacterium

In bacteria, the dynamics of chromosome replication and segregation are tightly coordinated with cell cycle progression, and largely rely on specific spatiotemporal arrangement of the chromosome. Whereas these key processes are mostly investigated in species that divide by binary fission, they remain mysterious in bacteria producing larger number of descendants. Here, we establish the predatory bacterium Bdellovibrio bacteriovorus as a model to investigate the non-binary processing of a circular chromosome. Our data reveal its extreme compaction in a dense polarized nucleoid. We also show that a first binary-like cycle of replication and asymmetric segregation is followed by multiple asynchronous rounds of replication and progressive ParABS-dependent partitioning, uncoupled from cell division. Surprisingly, ParB localization at the centromere is cell-cycle regulated. Altogether, our findings support a model of complex chromosome choreography, leading to the generation of variable numbers of offspring, highlighting the adaptation of conserved mechanisms to achieve non-binary reproduction in bacteria.

A REVIEW ON LIPOMA AND ITS GENETIC INTERVENTIONS

Lipomas are benign soft tissue fatty tumours that most commonly appear in the third decade of life when fatty tissue accumulates. Histologically, lipoma is composed of mature fat cells with a thin fibrous capsule. Simple lipomas account for 80% of adipose tissue tumours. The aetiology may be genetic like Familial Multiple Lipomatosis. Some tumours, like the well differentiated Liposarcomas never metastasize unless they undergo de-differentiation. They can be introduced as Atypical Lipomatous Tissue, ALT. Southern blot analysis is performed by obtaining DNA from ALT, cases in which most of them are characterized by the presence of supernumerary ring and long marker chromosomes. The complex chromosome region contains genes MDM2, CDK4, HMGI- C, SAS, GLI, CHOP, OS4 and OSP. Most of ALTs, after analysis revealed amplification of CDK4 and MDM2 proto- oncogenes that play major role in permitting over ride of block operated on cell proliferation. Immuno-histochemical results have shown MDM2 over expression in about 50% of ALTs along with weak CDK4 immuno-positivity. Also the lipomas with Gene fusion transcripts have the expression of certain genes, HMGA2/LPP, HMGA2/RDCI and HMGA2/NFIB. Of these 98% of cases were analyzed for the possible expression of HMGA2/LPP and LPP- HMGA2 fusion genes using reverse transcription polymerase chain reaction. Over all these cases, shows non-enhanced adipocyte apoptosis and enhanced adipogenesis in lipoma tissue. Thus studies provide insights into molecular pathogenesis of lipomatous tumour and representation of distinctive subset of mesenchymal neoplasms with mature adipocyte differentiation.

Nuclear Membrane Rupture and Its Consequences

The nuclear envelope is often depicted as a static barrier that regulates access between the nucleus and the cytosol. However, recent research has identified many conditions in cultured cells and in vivo in which nuclear membrane ruptures cause the loss of nuclear compartmentalization. These conditions include some that are commonly associated with human disease, such as migration of cancer cells through small spaces and expression of nuclear lamin disease mutations in both cultured cells and tissues undergoing nuclear migration. Nuclear membrane ruptures are rapidly repaired in the nucleus but persist in nuclear compartments that form around missegregated chromosomes called micronuclei. This review summarizes what is known about the mechanisms of nuclear membrane rupture and repair in both the main nucleus and micronuclei, and highlights recent work connecting the loss of nuclear integrity to genome instability and innate immune signaling. These connections link nuclear membrane rupture to complex chromosome alterations, tumorigenesis, and laminopathy etiologies.