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Abstract: Acute lymphoblastic leukemia is the most frequent pediatric malignancy in children, comprising 30% of all pediatric malignancies; adult ALL comprises 5% of all ALL cases, which have a 186.6 per 1 million incidence. In pediatric ALL (pALL), on which this review focuses, ap-proximately 1 in 285 children are diagnosed with cancer before the age of 20, and approximately 1 in 530 young adults between the ages of 20 and 39 years old is a childhood cancer survivor. The survival probability in pALL is now very high, approximately 80-90%. Thus, the most important is to improve supportive care and treatment based on relapse risk, optimally being based on the genet-ic feature of malignant cells. Improvements made by now are mainly the classifying of subgroups based on genetic characteristics such as aneuploidy or translocation and aligning them with treat-ment response. Relevant genetic changes in ALL pathogenesis are transcription regulators of lym-phoid development (PAX5, IKZF1, EBF1, and LEF1) and/or coactivators (TBL1XR1 and ERG), lymphoid signaling (BTLA, and CD200 TOX), and tumor suppressor genes (CDKN2A, CDKN2B, RB1, and TP53). This review aims to summarize treatment strategies inhibiting tyrosine kinases, in-fluencing different signaling pathways, BCL inhibitors, and anti-CD therapy (anti-cluster differenti-ation therapy) in pALL. CAR T-cell therapy (chimeric antigen receptors T-cell therapy) is under re-search and requires further development.

Acute lymphoblastic leukemia (ALL) is a malignant disease caused by mutations in B- or T-cell precursors of bone marrow cells. Childhood acute lymphoblastic leukemia (ALL) is a subtype of pediatric cancer with a 1 in 2000 incidence. Here we present a new childhood ALL in a 3-year-old girl. As CD45/19, CD10/19, CD3, CD8, CD10, and CD19 were positive in immunohistochemically analyses of blast cells, a B-ALL was diagnosed with a causative ETV6-RUNX1 gene fusion. The patient was treated based on standard protocols BMF-ALL 2009. Interestingly, an aunt and a grandfather of the patient had experienced malignancies as well, which may be carefully interpreted as a hint on a familial cancer syndrome.

Mucopolysaccharidosis type IIIB (MPS IIIB), also known as Sanfilippo syndrome type B, is a metabolic disease caused by mutations in both alleles of the NAGLU gene encoding for the enzyme α-N-acetylglucosaminidase. A malfunction of this enzyme causes inability to degrade heparan sulfate, which leads to accumulation of glycosaminoglycans in the cells. MPS IIIB is associated with different symptoms such as neurodegeneration, extreme hyperactivity, sleeping problems, aggressive behavior, reduced fear, and cognitive deterioration. The condition is by now not curable. Here we describe a patient with MPS IIIB diagnosed at the age of 5 presenting with communication problems, motor dysfunctions, and speech and sleeping problems. Standard biochemical tests for neurodegenerative disorders and DNA analyses including NAGLU mutation screening were performed. We also did some psychological tests assessing the patient’s communication skills and behavior. The patient was heterozygote for two mutations in the gene NAGLU (Y140C and Ser169fs). Thus, he suffered from MPS IIIB due to two mutations in the disease-causing gene. The patient presented with clear signs and symptoms of MPS IIIB with at least one of the two mutations affecting the α-N-acetylglucosaminidase protein function severely. Here we report the combination of a well-known and previously unreported mutation in the NAGLU gene; this could be dependent on geographical origin of the patient, which needs to be clarified by molecular studies of more MPS IIIB patients from Southeast Europe.&nbsp

The cell line MLTC-1 was established in 1982 as a transplantable Leydig cell tumor from a C57BL/6 mouse. The cell line has already been applied in >100 studies: still, the only information about its genetic content is given in the first description: MLTC-1 initially had a polyploid karyotype. Here, a molecular karyotyping and multicolor banding-based molecular cytogenetic study was done to provide the first chromosomal/ (molecular) cytogenetic characterization of MLTC-1. A hexaploid karyotype with 72 to 105 chromosomes was hereby characterized. Besides polyploidy, unbalanced two- and three-way translocations, dicentrics and one neocentric derivative were identified. Also, no Y-chromosome could be detected in this clearly male derived cell line. Overall, a completely unbalanced genome is present in MLTC-1 with ~20 regions being subject to copy number losses or gains. After translating these imbalances into the human genome in a standardized way, a 40% match of imbalances with human Leydig cell tumors was evident; however, about the same rate of concordance was detectable for human spermatocytic seminomas and non-seminomas as well as testicular germ cell tumor. Accordingly, MLTC-1 is better suited as an advanced testicular germ cell tumor model in general, rather than specifically for human Leydig cell tumors.

The Calmodulin Binding Transcription Activator 1 (CAMTA1) gene plays a central role in the human nervous system. Here evidence-based perspectives on its clinical value for the screening of CAMTA1 malfunction is provided and argued that in future, patients suffering from brain tumours and/or neurological disorders could benefit from this diagnostic. In neuroblastomas as well as in low-grade gliomas, the influence of reduced expression of CAMTA1 results in opposite prognosis, probably because of different carcinogenic pathways in which CAMTA1 plays different roles, but the exact genetics bases remains unsolved. Rearrangements, mutations and variants of CAMTA1 were associated with human neurodegenerative disorders, while some CAMTA1 single nucleotide polymorphisms were associated with poorer memory in clinical cases and also amyotrophic lateral sclerosis. So far, the follow-up of patients with neurological diseases with alterations in CAMTA1 indicates that defects (expression, mutations, and rearrangements) in CAMTA1 alone are not sufficient to drive carcinogenesis. It is necessary to continue studying CAMTA1 rearrangements and expression in more cases than done by now. To understand the influence of CAMTA1 variants and their role in nervous system tumours and in several psychiatric disorders is currently a challenge.

Retinoblastoma (RB) is the most common malignant intraocular tumor in children; it affects their eyes often even prenatally. RB may be sporadic or familial, due to germinal mutation in RB1 gene or by abnormal chromosomal abnormalities involving RB1 gene, located in 13q14. Monosomy of subband 13q14 as a partial deletion can also be responsible for RB with additional symptoms. The latter may be RB associated with psychomotor retardation, macrocephaly, broad forehead, thick earlobes, and bulbous nose.We present here the case of a boy from a consanguineous marriage with bilateral retinoblastoma, intellectual disability and facial dysmorphic features. Classical and molecular cytogenetics were used to recognize genotype-phenotype association.The karyotype showed a three way translocation involving chromosomes 5, 12 and 13. Further molecular cytogenetics analysis revealed a deletion of 13q14 involving the tumor suppressor gene RB1.This case highlights the impact of classical and molecular cytogenetics in diagnosis of rare genetic syndromes and for the genetic counselling of patients and their families. Pure molecular karyotyping analyses would miss the underlying chromosomal mechanism leading to the rearrangement.

Encouraging employees’ innovative behaviour (EIB) is one of the most important leadership tasks and numerous studies have examined the relationships between leadership and EIB. However, the research field is highly fragmented and does not provide a clear answer as to which leadership competencies are actually crucial for EIB. To address this issue, we use a qualitative content analysis to examine which leadership competencies are characterised in the literature as necessary for EIB. In doing so, we also turn away from broad leadership styles and adopt a behavioural-focussed competency approach. The results show that only a very small number of the many leadership competencies that seem to support EIB are considered necessary prerequisites for EIB. Based on the results, we present seven theoretical propositions and a concise model of leadership competencies necessary for EIB. In particular, we propose that the leadership competencies of providing support, communicating a vision, granting autonomy and discretion, and providing feedback are necessary conditions to enable EIB.

Mingkwan B, Sassi FDMC, Muanglenm N, Pinmongkhonkul S, Pinthong K, Tongnunui S, Yeesin P, Tanomtong A, Liehr T, Cioffi MDB, Supiwong W. 2023. Evolutionary tracks of chromosomal diversification in Trichopsis (Anabantiformes, Osphronemidae) fishes: New insights from a molecular cytogenetic perspective. Biodiversitas 24: 1551-1559. This study investigated the chromosomes of three Trichopsisspecies (namely Trichopsis pumila, Trichopsis vittata, and Trichopsis schalleri) using conventional (Giemsa stain, Ag-NOR) and molecularcytogenetic techniques. Fluorescence in situ hybridization (FISH) with repetitive DNAs, including 5S and 18S rDNAs, and microsatellites as probes were also performed. Our results indicated a conserved diploid number of 46 (2n) for all analyzed species of both sexes, although varying in their karyotype structure. Furthermore, T. schalleri and T. vittata karyotypes were presented with only acrocentric chromosomes (46a), while T. pumila had a submetacentric pair in addition to acrocentric ones (2sm+44a). Positive Ag-NOR sites were differentially found in each species adjacent to the acrocentric chromosome's centromeric and/or interstitial sub-centromeric regions. Both 5S and 18S rDNAs vary between the analyzed species, but all were localized in multiple sites. However, the distribution pattern of microsatellites differed in each species, mostly scattering at peri-centromeric and telomeric regions. These findings show that Trichopsis species, while having a conserved diploid number, differ significantly in the distribution of repetitive sequences in their karyotypes, particularly for rDNAs. These species-specific patterns can be useful for characterizing and identifying further different species and examining the evolutionary mechanisms that drove the evolution of these fishes' karyotypes.

Intrachromosomal amplification of chromosome 21 (iAMP21) occurs in ∼2% of B-cell acute lymphoblastic leukemia (ALL) and is considered to confer a poor prognosis. The relapse risk is associated with therapy intensity, suggesting that other somatic mutations may influence iAMP21-ALL prognosis. This abnormality is characterized by multiple copies of the RUNX1 gene in chromosome 21 and appears to arise through multiple breakage-fusion bridge cycles and chromothripsis. Rob(15;21) or a ring chromosome 21 have been associated with an increased risk for iAMP21-ALL, suggesting that constitutional genetic abnormalities may also drive leukemogenesis. Here we describe homozygous deletion of the SH2B3 gene, chromothripsis of chromosome 21, and a non-Robertsonian somatic t(15;21)(q25.3;q22.1) with NTRK3 gene rearrangement in an adolescent with iAMP21-B-ALL. Molecular cytogenetic studies detected iAMP21 with aCGH analysis revealing further genomic imbalances. The RT-qPCR analysis detected elevated expression levels of RUNX1 (68-fold) and reduced expression of CDK6 (0.057-fold). Studies with constitutive cells collected from mouth swabs showed that SH2B3 biallelic deletion was a somatic alteration occurring during clonal evolution. The identification of novel secondary genetic changes was valuable to discuss sporadic iAMP21 leukemogenic mechanisms. For the first time, we show a t(15;21)(q25.3;q22.1) with NTRK3 rearrangement in an adolescent with iAMP21-ALL.

Micromagnetic non-destructive (NDT) methods offer a great potential for the analysis of near-surface properties after machining due to potential time and cost reduction as well as the option to be implemented into the machining process. As a result, the development of soft sensor concepts including micromagnetic NDT methods is in focus of current investigations in order to eventually improve the surface integrity of machined components and, thus, service life and reliability. However, a preceding calibration based on empirical data as well as a reliable validation is often referred to as one of the main challenges of micromagnetic NDT methods. The present study provides insights into the calibration and validation of a micromagnetic 3MA-II system for NDT analysis of the near-surface properties, with a focus on the residual stress depth profiles after hard turning of 51CrV4 specimens. Different calibration functions as well as a combination of different NDT methods are taken into consideration. The results and the potential of the 3MA system as well as open challenges are critically discussed.

X-ray diffraction crystallography allows non-destructive examination of crystal structures. Furthermore, it has low requirements regarding surface preparation, especially compared to electron backscatter diffraction. However, up to now, X-ray diffraction has been highly time-consuming in standard laboratory conditions since intensities on multiple lattice planes have to be recorded by rotating and tilting. Furthermore, examining oligocrystalline materials is challenging due to the limited number of diffraction spots. Moreover, commonly used evaluation methods for crystallographic orientation analysis need multiple lattice planes for a reliable pole figure reconstruction. In this article, we propose a deep-learning-based method for oligocrystalline specimens, i.e., specimens with up to three grains of arbitrary crystal orientations. Our approach allows faster experimentation due to accurate reconstructions of pole figure regions, which we did not probe experimentally. In contrast to other methods, the pole figure is reconstructed based on only a single incomplete pole figure. To speed up the development of our proposed method and for usage in other machine learning algorithms, we introduce a GPU-based simulation for data generation. Furthermore, we present a pole widths standardization technique using a custom deep learning architecture that makes algorithms more robust against influences from the experiment setup and material.

About 25% of the patients with the translocation t(11;19)(q23;p13.3)/KMT2A-MLLT1 present three-way or more complex fusions, associated with a worse prognosis, suggesting that a particular mechanism creates functional KMT2A fusions for this condition. In this work, we show a cryptic three-way translocation t(9;11;19). Interestingly, long-distance inverse polymerase chain reaction sequencing revealed a KMT2A-MLLT1 and the yet unreported out-of-frame SEC16A-KMT2A fusion, associated with low SEC16A expression and KMT2A overexpression, in an infant with B-acute lymphoblastic leukemia presenting a poor prognosis. Our case illustrates the importance of molecular cytogenetic tests in selecting cases for further investigations, which could open perspectives regarding novel therapeutic approaches for poor prognosis childhood leukemias.

Background DiGeorge syndrome (DGS), caused by a deletion del(22)(q11.2q11.2), is the most frequently observed microdeletion syndrome. There is a vast clinical heterogeneity in DGS, and several studies suggested also heterogeneity of clinical signs and phenotypic appearance to be related to ethnic differences. Here, clinical characteristics of 72 patients with molecular diagnosed deletion del(22)(q11.2q11.2) derived from different countries from Europe, America, Africa, and Asia are summarized and compared. Results Unless ethnic differences, the expected major clinical signs were present in all cases. Frequent clinical manifestations found in this study were congenital heart disease with 68% (49/72), followed by dysmorphic features found in 61% (44/72); neurodevelopmental disorders were present in 43% (31/72) and thymus hypoplasia/aplasia in 32% (23/72). However, clinical features of the patients appeared/were recognized at different times during their lives. Within the group, under 2 years predominated heart disease, dysmorphic features, and hypocalcemia and/or hypoparathyroidism. In the group older than 2 years, the following combination of clinical findings was most frequent: dysmorphic features, congenital heart disease, intellectual disability, and immunological disorders. In the eight cases detected prenatally, abnormal sonographic findings were the major clinical signs (cardiovascular malformations and renal malformations). Conclusions Despite the heterogeneous nature of the sample analyzed, a number of clinical findings could be highlighted to be useful for the clinical delineation of this DGS. Interestingly, diagnostic indicators may vary depending on the age at diagnosis. Finally, apparent differences in DGS patients from different regions seem to be rather due to applied test systems than to real differences in patients from different ethnicities.

Teleost fishes exhibit a breath-taking diversity of sex determination and differentiation mechanisms. They encompass at least nine sex chromosome systems with often low degree of differentiation, high rate of inter- and intra-specific variability, and frequent turnovers. Nevertheless, several mainly female heterogametic systems at an advanced stage of genetic differentiation and high evolutionary stability have been also found across teleosts, especially among Neotropical characiforms. In this study, we aim to characterize the ZZ/ZW sex chromosome system in representatives of the Triportheidae family (Triportheus auritus, Agoniates halecinus, and the basal-most species Lignobrycon myersi) and its sister clade Gasteropelecidae (Carnegiella strigata, Gasteropelecus levis, and Thoracocharax stellatus). We applied both conventional and molecular cytogenetic approaches including chromosomal mapping of 5S and 18S ribosomal DNA clusters, cross-species chromosome painting (Zoo-FISH) with sex chromosome-derived probes and comparative genomic hybridization (CGH). We identified the ZW sex chromosome system for the first time in A. halecinus and G. levis and also in C. strigata formerly reported to lack sex chromosomes. We also brought evidence for possible mechanisms underlying the sex chromosome differentiation, including inversions, repetitive DNA accumulation, and exchange of genetic material. Our Zoo-FISH experiments further strongly indicated that the ZW sex chromosomes of Triportheidae and Gasteropelecidae are homeologous, suggesting their origin before the split of these lineages (approx. 40-70 million years ago). Such extent of sex chromosome stability is almost exceptional in teleosts, and hence, these lineages afford a special opportunity to scrutinize unique evolutionary forces and pressures shaping sex chromosome evolution in fishes and vertebrates in general.

Irreversible Electroporation (IRE) is a non-thermal tumor ablation treatment applicable for prostate cancer. IRE uses ultra-short but strong electrical pulses to destroy cancer cells nonthermally [1]. Clinically available IRE therapy requires two or more needle electrodes placed around the target tissue to apply the electric fields. A pre-requirement to achieve successful and effective ablation is an accurate and parallel needle placement to cover the tumor zone. Differences in tissue density, organ surface curvature as well as organ and patient motion in combination with long and highly flexible needle electrodes causes’ difficulties to achieve the desired target accuracy during needle placement process. We propose a concept of a shooting mechanism in combination with a grid template support to improve the parallel needle placement process for prostate cancer treatment. Instead of conventionally inserting the needle in the body by hand, it can be placed with high speed using a shooting device setup, that works similar like a biopsy gun.

Aim To examine the feasibility of using a 2-weekend Brief Culturally Tailored Thai Mindfulness intervention (BCTTMi) to affect stress, anxiety, and mindfulness in Thai parents of children with developmental disabilities (DDs), based on eight feasibility study criteria. Methods A BCTTMi was implemented with 22 Thai parents and caregivers of children with DDs with an experimental waitlist control crossover design. All participants were Thai and Buddhist; more than half had practiced meditation. The outcomes (stress, anxiety, mindfulness) were assessed with three Thai translated questionnaires, which had reported acceptable reliabilities. To address the feasibility criteria, data were gathered using virtual engagement, diary recordings, and a pre-, post-test trial. Results Assessment of the eight qualities of feasibility indicated: 1) acceptability: the BCTTMi appealed to the participants; 2) demand: the participants practiced mindfulness at home; 3) implementation: the mindfulness practitioner was qualified; 4) practicality: anxiety was the only outcome measure sensitive to the BCTTMi (p = .005); 5) adaptation: there was no attrition with the shortened mindfulness intervention; 6) integration: the BCTTMi may be included as part of the participants' routine club meeting; 7) expansion: a home visit and booster sessions may add strength; 8) limited efficacy: future work with 50 participants will allow adequate power when anxiety is the outcome. Conclusions Further studies testing the BCTTMi are warranted in broader populations and across varied settings. However, it will be important to do preliminary work to identify outcomes measures, other than anxiety, that are sensitive to the BCTTMi.

Variants in size of the acrocentric short arms (acro-ps) are normally not reported and considered as chromosomal heteromorphisms (CHMs) without any influence on the carrier’s phenotype. However, if acro-ps are translocated to ends of A-chromosomes (i.e. human chromosomes 1-22 and X or Y), those rearrangements are studied in more detail. The aim of the study: Here we characterized 11 healthy carriers of a non-acrocentric satellited chromosomes der(A)t(A;acro)(pter or qter;p1?1.2) to determine the frequency of chromosome 15p and 22p in such rearrangements. Materials and methods: 11 carriers of one (10 cases) or two (1 case) der(A)t(A;acro) were identified during routine cytogenetic analyses. They were originally referred due to infertility or due to a mentally retarded child with otherwise abnormal karyotype. Here derivative chromosomes were studied by fluorescence in situ hybridization applying probes D15Z1 (specific for 15p11.2) and D22Z4 (specific for 22p11.2). As there are no DNA-sequences available for 13p11.2, 14p11.2 and 21p11.2 these regions could not be tested. Results: D15Z1 sequences were identified in 1 out of 12 derivatives der(A)t(A;acro). D22Z1 could not be detected in any of the 11 remainder derivatives. However, only 3 of the 12 der(A)t(A;acro) had acro-ps large enough to potentially comprise sub-band p11.2. Conclusion: In contrast to der(Y)t(Y;acro)(q12;p1?1.2), where in at least 65% of the cases the acro-p part contains D15Z1 sequences, here it could be shown that in der(A)t(A;acro) 15p involvement can be substantiated much less frequently. Also, in none of the two groups D22Z4-sequences were detected in acro-p-parts yet. Besides, breakpoint of acro-pparts in der(A)t(A;acro) seem to be in ~75% of the cases distal from p11.2.

Phelan-McDermid syndrome (PHMDS) is a rare genetic disorder mostly caused by haploinsufficincy of SHANK3 gene, and characterized by neonatal hypotonia, developmental delay, minor dysmorphic features, seizures and behavior problems. Literature of this syndrome is scanty and confusing, and represents a challenge for pediatricians, in terms of finding the correct diagnoses.In a postnatal case with hypotonia and dysmorphic features a de novo ring chromosome r(22) leading to in parallel microdeletion and micro duplication in 22q13 was diagnosed by banding cytogenetics, and further characterized in detail by molecular cytogenetic and chromosomal microarray.Here a rare PHMDS case caused by a r(22) is presented. Less than 10 comparable cases are reported in the literature. The present case highlights the importance of conducting genetic counseling and appropriate genetic tests for newborns with mild dysmorphic features.

SummaryThe development of embryonic cell lineages is tightly controlled by transcription factors that regulate gene expression and chromatin organisation. To investigate the specialisation of 3D genome structure in pluripotent or extra-embryonic endoderm lineages, we applied Genome Architecture Mapping (GAM) in embryonic stem (ES) cells, extra-embryonic endoderm (XEN) stem cells, and in theirin vivocounterparts, the epiblast (Epi) and primitive endoderm (PrE) cells, respectively. We discover extensive differences in 3D genome topology including the formation domain boundaries that differ between Epi and PrE lineages, bothin vivoandin vitro, at lineage commitment genes. In ES cells,Sox2contacts other active regions enriched for NANOG and SOX2 binding sites. PrE-specific genes, such asLama1andGata6, form repressive chromatin hubs in ES cells.Lama1activation in XEN or PrE cells coincides with its extensive decondensation. Putative binding sites for OCT4 and SNAIL, or GATA4/6, distinguish chromatin contacts unique to embryonic or extra-embryonic lineages, respectively. Overall, 3D genome folding is highly specialised in early development, especially at genes encoding factors driving lineage identity.HighlightsES and XEN cells have specialised 3D genome structuresGAM applied in the blastocyst distinguishes Epi and PrE genome structuresLineage specific genes establish cell-type specific chromatin contactsSpecific chromatin contacts feature putative bindings sites for GATA4/6 in XEN cells and SNAIL in ES cells

Molecular combing technology (MCT) is an effective means for stretching DNA molecules and making them thus accessible for in situ studies. MCT uses the force exerted in the process of liquid flow via surface tension to stretch DNA molecules and spread them on solid surfaces, i.e. glass cover slips. Many DNA molecules can be stretched at the same time in parallel and neatly arranged side-by-side, making the approach convenient for statistical analysis. Accordingly, DNA replication and transcription can be studied at the single molecule level. In this paper, the principle, experimental methods, important applications, advantages and shortcuts of MCT in medical field are presented and discussed.

Phreatic explosions at volcanoes are difficult to forecast but can be locally devastating, as illustrated by the deadly 2019 Whakaari (New Zealand) eruption. Quantifying eruption likelihood is essential for risk calculations that underpin volcano access decisions and disaster response. But estimating eruption probabilities is notoriously difficult for sudden onset eruptions. Here, we describe two retrospectively developed models for short-term (48 h) probabilistic forecasting of phreatic eruptions at Whakaari. The models are based on a pseudo-prospective analysis of seven Whakaari eruptions whose precursors were identified by time series feature engineering of continuous seismic data. The first model, an optimized warning system, could anticipate six out of seven eruptions at the cost of 14 warning days each year. While a warning is in effect, the probability of eruption is about 8% in 48 h, which is about 126 times higher than outside the warning. The second model used isotonic calibration to translate the output of the forecast model onto a probability scale. When applied pseudo-prospectively in the 48 h prior to the December 2019 eruption, it indicated an eruption probability up to 400 times higher than the background. Finally, we quantified the accuracy of these seismic data-driven forecasts, alongside an observatory expert elicitation that used multiple data sources. To do this, we used a forecast skill score that was benchmarked against the average rate of eruptions at Whakaari between 2011 and 2019. This exercise highlights the conditions under which the three different forecasting approaches perform well and where potential improvements could be made.

Chromosomal heteromorphisms (CHs) are a part of genetic variation in man. The past literature largely posited whether CHs could be correlated with the development of malignancies. While this possibility seemed closed by end of the 1990s, recent data have raised the question again on the potential influences of repetitive DNA elements, the main components of CHs, in cancer susceptibility. Such new evidence for a potential role of CHs in cancer can be found in the following observations: (i) amplification and/or epigenetic alterations of CHs are routinely reported in tumors; (ii) the expression of CH-derived RNA in embryonal and other cells under stress, including cancer cells; (iii) the expression of parts of CH-DNA as long noncoding RNAs; plus (iv) theories that suggest a possible application of the "two-hit model" for euchromatic copy number variants (CNVs). Herein, these points are discussed in detail, which leads to the conclusion that CHs are by far not given sufficient consideration in routine cytogenetic analysis, e.g., leukemias and lymphomas, and need more attention in future research settings including solid tumors. This heightened focus may only be achieved by approaches other than standard sequencing or chromosomal microarrays, as these techniques are at a minimum impaired in their ability to detect, if not blind to, (highly) repetitive DNA sequences.

In acute myeloid leukemia (AML), treatment decisions are currently made according to the risk classification of the European LeukemiaNet (ELN), which is based on genetic alterations. Recently, optical genome mapping (OGM) as a novel method proved to yield a genome-wide and detailed cytogenetic characterization at the time of diagnosis. A young female patient suffered from a rather unexpected aggressive disease course under FLT3 targeted therapy in combination with induction chemotherapy. By applying a “next-generation diagnostic workup“ strategy with OGM and whole-exome sequencing (WES), a DDX3X: MLLT10 gene fusion could be detected, otherwise missed by routine diagnostics. Furthermore, several aspects of lineage ambiguity not shown by standard diagnostics were unraveled such as deletions of SUZ12 and ARPP21, as well as T-cell receptor recombination. In summary, the detection of this particular gene fusion DDX3X: MLLT10 in a female AML patient and the findings of lineage ambiguity are potential explanations for the aggressive course of disease. Our study demonstrates that OGM can yield novel clinically significant results, including additional information helpful in disease monitoring and disease biology.