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Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

The nucleosome, a basic unit of chromatin found in all eukaryotes, is thought to be assembled through the orchestrated activity of several histone chaperones and chromatin assembly factors in a stepwise manner, proceeding from tetrasome assembly, to H2A/H2B deposition, and finally to formation of the mature nucleosome. In this study, we demonstrate chaperone‐mediated assembly of both tetrasomes and nucleosomes on the well‐defined Widom 601 positioning sequence using a co‐expression/reconstitution wheat germ cell‐free system. The purified tetrasomes and nucleosomes were positioned around the center of a given sequence. The heights and diameters were measured by atomic force microscopy. Together with the reported unmodified native histones produced by the wheat germ cell‐free platform, our method is expected to be useful for downstream applications in the field of chromatin research., In this study, we developed a novel histone chaperone‐mediated assembly method for tetrasomes and nucleosomes using a wheat germ cell‐free co‐expression system. Drosophila tetrasomes and nucleosomes were assembled on the Widom 601 sequence under near physiological conditions. Purified tetrasomes and nucleosomes were assessed by gel analyses and evaluated by atomic force microscopy.

Background The presence of small supernumerary marker chromosomes (sSMCs) in a karyotype leads to diagnostic questions because the resulting extra material may cause abnormal development depending on the origin of the duplication/triplication. Because SMCs are so small, their origin cannot be determined by conventional cytogenetic techniques, and new molecular cytogenetic methods are necessary. Here, we applied a target approach to chromosome rearrangement analysis by isolating a chromosome of interest via microdissection and using it in fluorescence in situ hybridization (FISH) as a probe in combination with whole-chromosome painting probes. This approach allows to identify origins of both the euchromatin and repeat-rich regions of a marker. Case presentation We report a case of an adult male with congenital atresia of the rectum and anus, anotia, and atresia of the external auditory canal along with hearing loss. Karyotyping and FISH analysis with whole-chromosome painting probes of acrocentric chromosomes and the constructed microdissection library of the marker chromosome reliably identified an additional chromosome in some metaphases: mos 47,XY,+idic(22)(q11.2)[14]/46,XY [23]. Conclusion We propose to use whole-chromosome libraries and microdissected chromosomes in FISH to identify SMCs enriched with repeated sequences. We show that the methodology is successful in identifying the composition of a satellited marker chromosome.

Background Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures. Results We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses. Conclusion This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.

Tetrasomy 21 is a rare occurrence. Only 14 cases have been reported in the literature, 8 of which are partial tetrasomy cases and 6 which are complete tetrasomy cases. Of the incidences, no proband with true complete tetrasomy 21 has survived the neonatal period. We report complete mosaic tetrasomy 21 in a female infant with the typical Down syndrome phenotype, including Hirschsprung's disease and atrioventricular (AV) canal defect. This is in contrast to cases of partial tetrasomy 21, which often have an atypical trisomy 21 presentation and multiple nonspecific traits, including short stature, microcephaly, and developmental delays. This case demonstrates the difference in clinical presentation between the partial and complete subtype of tetrasomy 21 and provides the first postnatal clinical picture of an infant with true mosaic complete tetrasomy 21.

We report a 15-year-old boy with cat-eye syndrome (CES) without short stature or intellectual disorder. The boy was confirmed by cytogenetic and high-resolution chromosome microarray analysis (CMA). The G-banding karyotype confirmed the de novo of the patient. Also, the CMA result showed 1.76 Mb tetrasomy of proximal 22Q11.1 ⟶ 22Q11.21 consistent with CES {arr22q11.1q11.21 (16,888,899–18,644,241) X4}, a typical small type I CES chromosome. The patient has many of the basic characteristics of CES; however, he is taller than his peers instead of shorter. It is rarely reported in the past since short stature is a common feature of this syndrome. Furthermore, the boy has no intellectual disorder and attends a normal school since he was six-year-old. What bothered him most were recurrent respiratory infections, retromicrognathia, and heart defects.

Objective We present tetrasomy of 11q13.4-q14.3 due to an intrachromosomal triplication associated with paternal isodisomy of uniparental disomy (iso-UPD) for 11q14.3-qter and multiple abnormalities. Case report A 30-year-old primigravid woman was found to have intrauterine growth restriction (IUGR) in the fetus since 28 weeks of gestation, and a 2056-g baby was delivered at 38 weeks of gestation with fetal distress. The baby postnatally manifested hypotonia, microcephaly, facial dysmorphism of micrognathia, retrognathia and low-set ears, ventricular septal defect, atrial septal defect, tricuspid regurgitation and corpus callosum dysgenesis. A single nucleotide polymorphism (SNP) array comparative genomic hybridization analysis on the DNA extracted from the peripheral blood revealed the result of arr 11q13.4q14.3 (71,567,724–89,547,851) × 4, arr 11q14.3q25 (89,466,484–134,942,626) hmz [GRCh37 (hg19)] with a 17.980-Mb triplication of 11q13.4-q14.3 encompassing the genes of GRM5 and MAP6, and loss of heterozygosity for a 45.476-Mb region of 11q14.3-qter consistent with iso-UPD for 11q14.3-qter. Polymorphic DNA marker analysis confirmed paternal iso-UPD for 11q14.3-qter. Cytogenetic analysis of the blood revealed a karyotype of 46,XY,trp(11) (q13.4q14.3). The parental karyotypes were normal. When follow-ups at age 2 years, the neonate manifested physical and psychomotor developmental delay and intellectual disability. Conclusion Tetrasomy 11q13.4-q14.3 may present the phenotype of IUGR, developmental delay, corpus callosum dysgenesis, microcephaly, congenital heart defects and facial dysmorphism.

An intact DNA damage response is crucial to preventing cancer development, including in myeloid and lymphoid malignancies. Deficiencies in the homologous recombination (HR) pathway can lead to defective DNA damage responses, and this can occur through inherited germline mutations in HR pathway genes, such as CHEK2 and ATM. We now understand that germline mutations can be identified frequently (~ 5-10%) in patients with myeloid and lymphoid malignancies, and among the most common of these are CHEK2 and ATM. We review the role that deleterious germline CHEK2 and ATM variants play in the development of hematopoietic malignancies, and how this influences clinical practice, including cancer screening, hematopoietic stem cell transplantation, and therapy choice.In recent large cohorts of patients diagnosed with myeloid or lymphoid malignancies, deleterious germline loss of function variants in CHEK2 and ATM are among the most common identified. Germline CHEK2 variants predispose to a range of myeloid malignancies, most prominently myeloproliferative neoplasms and myelodysplastic syndromes (odds ratio range: 2.1-12.3), and chronic lymphocytic leukemia (odds ratio 14.83). Deleterious germline ATM variants have been shown to predispose to chronic lymphocytic leukemia (odds ratio range: 1.7-10.1), although additional studies are needed to demonstrate the risk they confer for myeloid malignancies. Early studies suggest there may also be associations between deleterious germline CHEK2 and ATM variants and development of clonal hematopoiesis. Identifying CHEK2 and ATM variants is crucial for the optimal management of patients and families affected by hematopoietic malignancies. OPENING CLINICAL CASE: "A 45 year-old woman presents to your clinic with a history of triple-negative breast cancer diagnosed five years ago, treated with surgery, radiation, and chemotherapy. About six months ago, she developed cervical lymphadenopathy, and a biopsy demonstrated small lymphocytic leukemia. Peripheral blood shows a small population of lymphocytes with a chronic lymphocytic leukemia immunophenotype, and FISH demonstrates a complex karyotype: gain of one to two copies of IGH and FGFR3; gain of two copies of CDKN2C at 1p32.3; gain of two copies of CKS1B at 1q21; tetrasomy for chromosome 3; trisomy and tetrasomy for chromosome 7; tetrasomy for chromosome 9; tetrasomy for chromosome 12; gain of one to two copies of ATM at 11q22.3; deletion of chromosome 13 deletion positive; gain of one to two copies of TP53 at 17p13.1). Given her history of two cancers, you arrange for germline genetic testing using DNA from cultured skin fibroblasts, which demonstrates pathogenic variants in ATM [c.1898 + 2 T G] and CHEK2 [p.T367Metfs]. Her family history is significant for multiple cancers. (Fig. 1)." Fig. 1 Representative pedigree from a patient with germline pathogenic ATM and CHEK2 variants who was affected by early onset breast cancer and chronic lymphocytic leukemia. Arrow indicates proband. Colors indicate cancer type/disease: purple, breast cancer; blue, lymphoma; brown, melanoma; yellow, colon cancer; and green, autoimmune disease.

Whole-genome duplication (WGD) is hypothesized to be an important evolutionary mechanism that can facilitate adaptation and speciation. Genomes that exist in states of both diploidy and residual tetraploidy are of particular interest, as mechanisms that maintain the ploidy mosaic after WGD may provide important insights into evolutionary processes. The Salmonidae family exhibits residual tetraploidy, and this, combined with the evolutionary diversity formed after an ancestral autotetraploidization event, makes this group a useful study system. In this study, we generate a novel linkage map for cisco (Coregonus artedi), an economically and culturally important fish in North America and a member of the subfamily Coregoninae, which previously lacked a high-density haploid linkage map. We also conduct comparative genomic analyses to refine our understanding of chromosomal fusion/fission history across salmonids. To facilitate this comparative approach, we use the naming strategy of protokaryotype identifiers (PKs) to associate duplicated chromosomes to their putative ancestral state. The female linkage map for cisco contains 20,292 loci, 3,225 of which are likely within residually tetraploid regions. Comparative genomic analyses revealed that patterns of residual tetrasomy are generally conserved across species, although interspecific variation persists. To determine the broad-scale retention of residual tetrasomy across the salmonids, we analyze sequence similarity of currently available genomes and find evidence of residual tetrasomy in seven of the eight chromosomes that have been previously hypothesized to show this pattern. This interspecific variation in extent of rediploidization may have important implications for understanding salmonid evolutionary histories and informing future conservation efforts.

Background Small supernumerary marker chromosomes (sSMCs), are additional abnormal chromosomes, which can’t be detected accurately by banding cytogenetic analysis. Abnormal phenotypes were observed in about 30% of SMC carriers. Duplication of chromosome 15 and related disorders, characterized by hypotonia motor delays, autism spectrum disorder (ASD), intellectual disability, and epilepsy including infantile spasms, might be account for 50% of the total sSMCs. Case presentation An 11-month-old infant with an sSMC found by banding cytogenetics was referred to our clinic because of developmental retardation and autism spectrum disorder. After several months of rehabilitation treatment, the progress of motor development was obvious, but the consciousness was still far from satisfied. High-resolution karyotype analysis, multiplex ligation-dependent probe amplification and copy number variation sequencing (CNV-Seq) were conducted to confirm the identity of the sSMC. A bisatellited dicentric sSMC was observed clearly in high-resolution karyotype analysis and a 10.16-Mb duplication of 15q11.1q13.2 (3.96 copies) together with a 1.84-Mb duplication of 15q13.2q13.3 (3 copies) was showed by CNV-Seq in the proband. It suggested that the molecular cytogenetic karyotype was 47,XY,+dic(15;15)(q13.2;q13.3). Furthermore, the clinical symptoms of the proband mostly fit 15q duplication related disorders which are characterized by hypotonia motor delays, autism spectrum disorder (ASD), and intellectual disability. Conclusion We reported for the first time using CNV-Seq to detect sSMCs and find a partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder. Our report indicates that CNV-seq is a useful and economical way for diagnosis of dup15q and related disorders.

Introduction. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is rare and very aggressive hematological malignancy derived from precursor of the plasmocytoid dendritic cell (pDC). We present a case with cervix uteri involvement without skin lesions, and to our knowledge, it is the first case of BPDCN localized in the cervix. Case Outline. A 66 year-old, previous healthy woman, initially presented with a 4-weeks history of vaginal bleeding. Gynaecological examination showed tumorous bleeding formation on cervix uteri. Except paleness of skin, the physical examination was normal. Complete blood counts showed anaemia and thrombocytopenia. Computed tomography (CT) scans disclosed expansive tumorous formation in the level of the isthmus and cervix uteri 60x42mm in diameter. Cervical biopsy was done and final pathohistological diagnosis was BPDCN. Karyotype analysis results from the bone marrow aspiration specimen demonstrated tetrasomy of chromosome 2 and monosomy of chromosome 16. The patient did not accept treatment and died two months after initial diagnosis was established. Conclusion. Attributes as aggressive clinical course of BPDCN, demonstrated unusual localisation, infrequency and the absence of consensus about standard treatment options, demand constructive clinical reasoning and tight cooperation between medical professionals of various fields.

Haematopoietic malignancies are frequently characterized by karyotypic abnormalities. The development of targeted drugs has been pioneered with compounds against gene products of fusion genes caused by chromosomal translocations. While polysomies are equally frequent as translocations, for many of them we are lacking therapeutic approaches aimed at synthetic lethality. Here, we report two new cell lines, named MBU-7 and MBU-8, that differ in complete trisomy of chromosome18, a partial trisomy of chromosome 7 and a tetrasomy of the p-arm of chromosome 8, but otherwise share the same mutational pattern and complex karyotype. Both cell lines are divergent clones of U-937 cells and have the morphology and immunoprofile of monocytic cells. The distinct karyotypic differences between MBU-7 and MBU-8 are associated with a difference in the specific response to nucleoside analogues. Taken together, we propose the MBU-7 and MBU-8 cell lines described here as suitable in vitro models for screening and testing vulnerabilities that are associated with the disease-relevant polysomies of chromosome 7, 8 and 18.

Here, we report a case of Acute promyelocytic leukemia (APL) with three way complex translocation involving chromosomes 4, 15, and 17. Although chromosome 4 is most commonly associated chromosome in three way translocation, present case is the first report with four novel co-existent findings of new break point region on chromosome 4, new cyclic mechanism with simultaneous breaks, presence of a co-existent tetrasomy 8 and FLT3 ITD positivity.; Comprehensive assessment highlight the utility of combining morphology, immunophenotyping, karyotyping, fluorescence in situ hybridization, and molecular studies for better characterization, optimal management of APL with a better understanding of the pathogenic mechanism and prognosis of the disease.

Background: Noninvasive prenatal genetic testing (NIPT) has been adopted as the first choice for aneuploidy screening. The purposes of this study were to investigate the accuracy of Vanadis® NIPT (hereafter CRITO-NIPT) in order to gain a deeper insight into the reasons for discrepancies, as well as to discuss the role of fetal ultrasound. Methods: Between 2019 and 2020, CRITO-NIPT was performed in 1218 cases of patients who underwent CVS or amniocentesis after a detailed fetal ultrasound exam and genetic counseling. The CRITO-NIPT results were compared with the genetic results. In cases of test discrepancies, the placentae were collected for detailed genetic research, and the pre-procedure fetal ultrasound findings were referred to. Results: The positive predictive value of T21, T18, and T13 was 93.55%, 88.46%, and 100%, respectively. In 90% of the of false positive (FP) cases, the placentae were examined. In 75% of the CRITO FP-T21 cases, placental mosaicism, or a demised twin’s T21, were confirmed. There were complicated mosaic cases, including tetrasomy 21/trisomy7 and monosomy 21/trisomy21 cases. In one of three no-call cases, an intermediate deletion of chromosome 13 was detected. Conclusions: The CRITO study investigated the mechanism of false positives, and the detailed mechanisms in mosaic and no-call cases. There have hitherto been no reports that have provided insight by partitioning the placenta to compare the NIPT and invasive test results, nor that have provided detailed ultrasound findings in the cases of discordant results, revealing the demonstrated importance of, and necessity for, detailed ultrasonography. This article describes the potential of rolling-circle replication as a powerful biosensing platform, as well as the importance of examining the fetus in detail with ultrasound. However, we should remember that the potential applications raise ethical and social concerns that go beyond aneuploidy and its methodology.

Aim To detect the frequency, diagnostic and prognostic significance of 11q23/MLL rearrangements and to determine the chromosomes that are most frequently involved in 11q23/MLL abnormalities in adult acute leukemia (AL). Materials and methods Cytogenetic investigations of bone marrow and/or peripheral blood cells from 140 patients with acute myeloid leukemia (AML) and 57 patients with acute lymphoblastic leukemia (ALL) were performed. The methods of conventional cytogenetics (GTG-banding) and fluorescence in situ hybridization were used. Results Chromosomal abnormalities in leukemia cells were found by conventional cytogenetic methods in 80 (57%) and 37 (65%) adult patients with AML and ALL, respectively. 11q23/MLL rearrangements were found in 7 (5%) and 8 (14%) patients with AML and ALL, respectively. Among them, 8 (53.4%) patients had translocations, 2 (13.3%) - had deletions and 5 (33.3%) patients had trisomies or tetrasomies of chromosome 11. With respect to the distribution of partner chromosomes involved in 11q23/MLL translocations chromosome 4 was found to participate in 3 (37.5%) cases of 11q23/MLL translocations, 9 - in 2 (25%) cases and chromosomes 10, 14 and non-identified chromosome were involved in 1 (12.5%) case each. Nine patients (60%), besides abnormal ones, had 9-86% normal metaphases in their karyotypes. Of 15 patients with 11q23/MLL rearrangements, 5 (33%) patients had only 11q23/MLL rearrangements, whereas other 10 (67%) - had additional cytogenetic abnormalities, besides 11q23/MLL rearrangements. Conclusions Chromosomal abnormalities of various kinds were found in 57% and 65% adult patients with AML and ALL, respectively. The frequency of 11q23/MLL rearrangements in patients with AML and ALL was 5% and 14%, respectively. Since AL patients with 11q23/MLL rearrangements are attributed to cytogenetic categories of AL with a poor or intermediate risk prognosis, cytogenetic methods should be included in the standard examination of AL patients for diagnosis, prognosis and selection of the optimal treatment strategy.

BACKGROUND Spontaneous intracranial hypotension has historically been a poorly understood pathology that is often unrecognized and undertreated. Even more rarely has it been described in pediatric patients with an otherwise benign past medical history. OBSERVATIONS Herein the authors describe one of the youngest patients ever reported, a 2-year-old girl who developed severe headaches, nausea, and vomiting and experienced headache relief after lying down. Imaging revealed tonsillar herniation 14 mm below the foramen magnum, presumed to be a Chiari malformation, along with extensive dural cysts starting from thoracic level T2 down to the sacrum. She was found to have streaky skin pigmentary variation starting from the trunk down to her feet. Genetic analysis of skin biopsies revealed mosaicism for an isodicentric marker chromosome (10p15.3–10q11.2 tetrasomy) in 27%–50% of cells. After undergoing a suboccipital and cervical decompression at an outside institution, she continued to be symptomatic. She was referred to the authors’ hospital, where she was diagnosed with spontaneous intracranial hypotension. LESSONS After receiving a series of epidural blood patches, the patient experienced almost complete relief of her symptoms. To the authors’ knowledge, this is the first time this chromosomal anomaly has ever been reported in a living child, and this may represent a new genetic association with dural ectasia.

The genetic basis of inflammatory bowel disease remains to be elucidated completely. Here we report on a patient with inflammatory bowel disease who has mosaic tetrasomy of the short arm of chromosome 9, a genomic region that harbours the type I interferon gene cluster. We show that increased interferon activation is present in peripheral blood and intestinal tissue from this patient, similar to previous reports of autoinflammatory organ damage driven by interferon activation in other patients with this chromosomal abnormality. To our knowledge, this is the first case of tetrasomy 9p-associated interferonopathy driving intestinal inflammation and highlights the role that type-I interferon pathways can play in the pathogenesis of intestinal inflammation.

Whole-genome duplications (WGDs) have occurred repeatedly and broadly throughout the evolutionary history of eukaryotes. However, the effects of WGD on genome function and evolution remain unclear. The salmonid WGD that occurred approximately 88 million years ago presents an excellent opportunity for studying the effects of WGD as ∼10–15% of each salmonid genome still exhibits tetrasomic inheritance. Herein, we utilized the rainbow trout (Oncorhynchus mykiss) genome assembly and brain transcriptome data to examine the fate of gene pairs (ohnologs) following the salmonid whole-genome duplication. We find higher sequence identity between ohnologs located within known tetrasomic regions than between ohnologs found in disomic regions, and that tetrasomically inherited ohnologs showed greater similarity in patterns of gene expression and per ohnolog were lower expressed, than disomically inherited ohnologs. Enrichment testing for Gene Ontology terms identified 49 over-represented terms in tetrasomically inherited ohnologs compared to disomic ohnologs. However, why these ohnologs are retained as tetrasomic is difficult to answer. It could be that we have identified salmonid specific “dangerous duplicates”, that is, genes that cannot take on new roles following WGD. Alternatively, there may be adaptive advantages for retaining genes as functional duplicates in tetrasomic regions, as presumably, movement of these genes into disomic regions would affect both their sequence identity and their gene expression patterns.

Here, we report a molecular characterization of a small supernumerary marker chromosome (sSMC) derived from the most proximal region of 13q present in a fetus with coarctation of the aorta at ultrasound examination during prenatal diagnosis. Cultured umbilical cord blood cells showed a de novo extra ring-shaped sSMC in 76% of the cells using a standard banding technique. SNP array revealed a tetrasomy of about 28.4 Mb in the long arm of chromosome 13 from band 13q11 to 13q14.11 in the fetus's cells. Metaphase/interphase FISH using specific probes located at 13q11, 13q12.11, and 13q14.11, respectively, demonstrated that the supernumerary ring chromosome was derived from an inverted duplication of the region 13q11q14.11 with a conventional centromere. To the best of our knowledge, this is the first time that an inverted duplication of the most proximal region 13q11q14.11 in a ring chromosome is characterized. The findings we presented here deepen our understanding of the clinical consequences of tetrasomy in this region and may be of help for further studies of critical regions in chromosome 13.

Pallister-Killian mosaic syndrome (PKS) is a rare sporadic condition with multiple congenital anomalies and intellectual deficits caused by mosaic tissue-limited tetrasomy of the short arm of chromosome 12 (12p). The clinical features are highly variable, ranging from mild to severe. Diagnosis is usually missed because of the low level of mosaicism in peripheral lymphocytes. We present a case of an Omani newborn with PKS with severe clinical presentation and multisystem involvement that lead to postnatal death. Karyotype and fluorescent in situ hybridization studies confirmed the presence of chromosome 12p duplication. This is the first case of PKS reported in the literature from Oman and the Arab world.

Pallister–Killian syndrome (PKS) is a rare, sporadic disorder defined by a characteristic dysmorphic face, pigmentary skin anomalies, intellectual disability, hypotonia, and seizures caused by 12p tetrasomy due to an extra isochromosome 12p. We present three cases of PKS and two cases of trisomy 12p to illustrate and discuss features rarely cited in the literature, present certain particularities that not yet been cited, and analyze the differences between entities. Moreover, we present alternative methods of diagnosis that could be easily used in daily practice. Features not yet or rarely reported in PKS literature include marked excess of hair on the forehead and ears in the first months of life, a particular eye disorder (abnormal iris color with pointed pupil), connective tissue defects, repeated episodes of infection and autonomic dysfunction, endocrine malfunction as a possible cause of postnatal growth deficit, more complex sensory impairments, and mild early myoclonic jerks. After performing different combinations of tests, we conclude that MLPA (follow-up kit P230-B1) or array CGH using DNA extracted from a buccal swab is a reliable method of diagnosis in PKS and we recommend either one as a first intention diagnostic test. In cases without major defects associated (suspicion trisomy 12p), subtelomeric MLPA should be performed first.

Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress, and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.

Tetrasomy 9p (ORPHA:3390) is a rare syndrome, hallmarked by growth retardation, psychomotor delay, mild to moderate intellectual disability, and a spectrum of skeletal, cardiac, renal and urogenital defects. Here we present a Chinese female with good past health who conceived her pregnancy naturally. Non-invasive prenatal testing (NIPT) showed multiple chromosomal aberrations were consistently detected in two sampling times, which included elevation in DNA from chromosome 9p. Amniocentesis was performed and sent for chromosomal microarray, which was normal. Maternal karyotype revealed that mos 47,XX,+dic(9, 9)(q21.1, q21.1)(24)/46,XX(9) presents mosaic tetrasomy for the short arm of chromosome 9p and is related to the NIPT results showing elevation in DNA from chromosome 9p. The pregnancy was uneventful, and the patient was delivered at term. Maternal samples were obtained at two different time points after delivery showed the same multiple chromosomal aberrations detected during pregnancy. This is a first report on an unusual case of mosaic isodicentric tetrasomy 9p in a healthy adult with normal intellect. With widespread adoption of NIPT for screening fetal aneuploidy and genome-wide copy number changes, a rise in incidental detection of maternal rare genetic syndrome will bring challenges in our current approach to genetic counselling and prenatal diagnosis.

Klinefelter syndrome (KS) variants often share common features with classical syndrome but some of these variants present with a distinct phenotype. The incidence of sex chromosome tetrasomy and pentasomy are very less and generally diagnosed after prepubertal age. The early diagnosis of complex and unclassified syndromes and it's correlation with genotype is necessary for personalized treatment as well as genetic counselling of the affected families. We describe clinical presentation, and genetic diagnosis of two cases of variant KS. Our first case, a 4 year old male child presented with generalized tonic-clonic seizures (GTCSs), delayed milestones and dysmorphic features while case 2, a-21 years old male who had history of seizures and delayed puberty came to our lab for genetic diagnosis. The chromosomal analysis of case 1 and 2 showed 49,XXXXY and 48,XXYY karyotype respectively. The karyotype results were confirmed with fluorescence in situ hybridization (FISH) and array-CGH analysis. The FISH results were found to be consistent with karyotype but the array-CGH results showed the extra gain of region Yp11.2 in case 1 while the extra gain of region Xp22.33 in case 2. The cases were confirmed as variant KS on the basis of additional sex chromosomes and clinical presentation of deteriorated brain development. The present study suggests that the high doses of sex chromosome linked genes including pseudoautosomal region (PAR) caused the abnormal brain development. The combination of molecular techniques should be utilized for the diagnosis of such complex cases to understand the genotype-phenotype correlation and appropriate genetic counseling.

Pallister-Killian syndrome (PKS) is a rare disorder presenting with developmental delay, numerous dysmorphic features, and skin pigmentation anomalies. It is caused by mosaic tetrasomy of the short arm of chromosome 12. In most instances, tetrasomy is due to a supernumerary isochromosome i(12)(p10). Although mitotic instability is a generally accepted behavior for supernumerary chromosomes, hexasomy 12p due to a gain of an isochromosome 12p, has been hardly ever reported. We report a 10 year follow-up on a girl with 2 copies of isochromosome consisting of the short arm of chromosome 12, who has craniofacial features seen in PKS, such as sparse hair with an unusual pattern, sparse eyebrows, lacrimal duct stenosis, submucous cleft palate, Pallister lip (a relatively long philtrum continuing into the vermillion border of the upper lip), narrow palate, and wide alveolar ridges. She also has other abnormalities, including unilateral renal dysgenesis, rectovaginal fistula, pre-axial polydactyly of the right hand, severe global developmental delay, and hypotonia as well as some features suggestive of mosaicism such as bilateral asymmetry, patchy areas of rough skin, and retinal mottling. Initial cytogenetic studies from peripheral blood showed a normal female karyotype. Further cytogenetic studies on a skin biopsy showed mosaicism with 2 copies of the supernumerary isochromosome 12p.

Background Terminal duplication on chromosome 15q is a rare chromosomal variation. Affected individuals show similar features such as growth dysplasia or the development of frontal bossing, body deformities, facial abnormalities, and genitourinary or cardiovascular disorders. However, it is not yet clear whether such 15q repeats lead to identifiable patterns of clinical abnormalities. Therefore, the purpose of this study was to analyze the prenatal diagnostic results and clinical manifestations of a fetus with 15q duplication and to summarize the literature. Methods The case was a fetus at 28 weeks of gestation. The risk of Down syndrome from second‐trimester screening was 1/140. Prenatal ultrasound and amniocentesis were performed, and chromosomal microarray analysis (CMA) was used for genetic analysis. Results The fetus had abnormal clinical features, including intracardiac echogenic focus in the left ventricle, an aberrant right subclavian artery, and growth delay. The fetal chromosomal karyotype was 46,XX,15q?,12q?,21pstk+, and CMA revealed a 10.163 Mb duplication at 15q24.3‐q25.3. The couple chose to terminate the pregnancy after careful consideration. Conclusions The combination and rational application of cytogenetics technology and molecular genetics technology such as CMA will open up the field of clinical application and provide useful genetic counseling for parents of fetuses carrying such chromosomal duplications.

Pediatric acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) that may be divided into two subgroups: (1) Down syndrome- (DS-) related AMKL which generally has a favorable prognosis and (2) non-DS-related AMKL which generally has a poorer outcome. We report a phenotypically normal child with AMKL with trisomy 21 (T21) and tetrasomy 21 clones. Subsequently, she was diagnosed with mosaic T21. She underwent reduced-intensity therapy with good outcome. We review the literature regarding AMKL-associated cytogenetic abnormalities and AMKL in association with DS. We suggest evaluation for mosaic T21 in phenotypically normal pediatric patients with T21-positive AML.

Background Tetrasomy 18p is a rare disorder. It is known to affect about 250 families worldwide. Tetrasomy 18p is also the most common type of isochromosome. Here we report a de novo tetrasomy 18p. Methods The copy number variation of the patient was detected by microarray. Whether the abnormal gene was inherited from the parents was detected by karyotype analysis. Then the source of the chromosome was located by fluorescence in situ hybridization. Finally, we used MLPA technology to validate the results of patient testing. Results Microarray detection found that patients with 18p11.32p11.21 had duplication, with a copy number of four, which was tetrasomy 18 syndrome. The karyotype results showed 48,XY,+2mar?. Chromosome 18 telomere probe FISH experimental results: 48,XY,+i(18)(p10),+mar.ish. MLPA results showed that the number of chromosome 18 short arm copies is increased. Karyotype analysis results of his mother were 47,XX,+mar. Microarray results showed normal. Karyotype results of his father were normal. Conclusions This case is de novo case, the patient's marker chromosome may be inherited from his mother, which does not rule out the influence of his mother's marker chromosome on his isochromosome 18.

Background: RUNX1 is a crucial transcription factor for hematological stem cells and well-known for its association with acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). Besides the translocation t(8; 21) that leads to the RUNX1-RUNX1T1 fusion, somatic mutations of RUNX1 have been discovered. Methods: Four bone marrow trephine biopsies of patients with CD79a-positive and/or PAX5-positive acute leukemias were investigated by immunohistochemistry (IHC), karyotyping, and next-generation sequencing-based genetic analysis. Data were then compared to a historical collective of AML (n = 42) and 42 cases of AML newly diagnosed at our institution between June 2017 and May 2018. Results: We report on 4 cases of acute leukemia with an equivocal immunophenotype showing expression of CD79a and/or PAX5, which led to a preliminary histopathologic classification as probable ALL/unclassifiable acute leukemia. All cases were positive for CD34 and TdT but negative for several myeloid markers on IHC. Mutational analysis revealed point mutations and indels of RUNX1 and further mutations typical for AML such as TET2, DNMT3A, and SRSF2, and 2 cases had tetrasomy 13 characteristic of RUNX1 mutant AML. Conclusion: Aberrant CD79a and/or PAX5 expression can be found in AML cases with RUNX1 mutations even without the translocation t(8; 21). Our series shows the expression of CD79a and PAX5 to be a potential pitfall in the classification of RUNX1 mutant acute leukemia.

Background: Pallister Killian syndrome (PKS, OMIM 601803) is a rare genetic disorder with a distinct phenotype caused by tissue-limited mosaicism tetrasomy of the short arm of chromosome 12, which usually cytogenetically presents as an extra isochromosome 12p. Wide phenotypic variability in PKS has been reported, ranging from pre-to perinatal death due to multiple congenital anomalies, especially diaphragmatic hernia, and classic phenotypes including seizures, severe developmental delay, macrosomia at birth, deafness, and distinct dysmorphic features, such as coarse face, temporal alopecia, a small nose with anteverted nostrils, long philtrum, and hypo-/hyper- pigmented streaks on the skin. Results: Karyotypes obtained from cultured peripheral lymphocytes of 13 cases, who were diagnosed as PKS, were normal, while karyotypes obtained from cultured skin samples and buccal mucosa revealed the supernumerary mosaic i(12p). Mosaic karyotype was found in both fibroblast and buccal mucosa in 14 of 15 patients in our series, whereas in one stillbirth, following the clinical diagnosis of PKS, skin and buccal smear samples were taken, and all karyotypes from cultured fibroblasts revealed a supernumerary i(12p), while I-FISH study showed 60% mosaicism in mucosal cells. Conclusions: We here share the clinical, cytogenetic and molecular cytogenetic findings of 15 cases with PKS phenotype and the parental origin of seven i(12p) identified by molecular analyses. To our knowledge, this is the largest series of PKS patients with parental origin study from a single center. We believe that our study makes a significant contribution to the literature because we specifically found no differences in the phenotypes of cases with either a maternal or paternal origin of the extra element and differential imprinting appeared not to be a factor., NA

Abstract: Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder that is caused by the mosaic presence of a supernumerary marker chromosome, isochromosome 12p. The syndrome is a polydysmorphic condition characterized by mental retardation, craniofacial dysmorphism, hypotonia, seizures, epilepsy and certain organic malformations (diaphragmatic hernia, congenital heart disease). Prenatal diagnosis is challenging due to the mosaic tissue-specific distribution of the chromosomal disorder and highly variable phenotype. Prenatal diagnosis is often accidental, however, appropriate laboratory techniques based on the second trimester ultrasound anomalies provide accurate prenatal diagnosis. We report a case of a 36-year-old primipara with second trimester ultrasound markers (polyhydramnion, ventriculomegaly, rhizomelic micromelia, abnormal facial profile). The patient underwent amniocentesis, the conventional karyotyping revealed a supernumerary chromosome in nearly 50 percent of amniocytes. FISH and targeted multicolour FISH probes verified mosaic tetrasomy of the short arm of chromosome 12 of the fetus. Fetopathological examinations and analysis of fetal tissues and blood confirmed the prenatal diagnosis. To our knowledge, this is the first reported case of prenatally diagnosed Pallister–Killian syndrome in Hungary. Orv Hetil. 2018; 159(21): 847–852.

Though polyploidy is an important aspect of the evolutionary genetics of both plants and animals, the development of population genetic theory of polyploids has seriously lagged behind that of diploids. This is unfortunate since the analysis of polyploid genetic data-and the interpretation of the results-requires even more scrutiny than with diploid data. This is because of several polyploidy-specific complications in segregation and genotyping such as tetrasomy, double reduction, and missing dosage information. Here, we review the theoretical and statistical aspects of the population genetics of polyploids. We discuss several widely used types of inferences, including genetic diversity, Hardy-Weinberg equilibrium, population differentiation, genetic distance, and detecting population structure. For each, we point out how the statistical approach, expected result, and interpretation differ between different ploidy levels. We also discuss for each type of inference what biases may arise from the polyploid-specific complications and how these biases can be overcome. From our overview, it is clear that the statistical toolbox that is available for the analysis of genetic data is flexible and still expanding. Modern sequencing techniques will soon be able to overcome some of the current limitations to the analysis of polyploid data, though the techniques are lagging behind those available for diploids. Furthermore, the availability of more data may aggravate the biases that can arise, and increase the risk of false inferences. Therefore, simulations such as we used throughout this review are an important tool to verify the results of analyses of polyploid genetic data.

Small supernumerary marker chromosomes (sSMCs) are chromosomal fragments or markers whose origins often requires both conventional cytogenetic methods and molecular approaches for a characterization. Chromosomal Microarray Analysis (MCA) and fluorescence in situ hybridization (FISH) provide accurate characterization of sSMCs in terms of chromosomal origin, gene content and other additional imbalances elsewhere in the genome. sSMCs have been reported to be present in ~0.043% of live births and ~0.075% prenatal cases, are seven times more prevalent in intellectually disabled patients, with a frequency of 0.125% in individuals presenting infertility. Approximately 70% of SMCs are de novo and 30% are inherited, either from the mother (20%) or the father (10%). The implication of sSMC could be due to partial trisomy or tetrasomy of some genes and the effects on the phenotype is difficult to define. It depends on factors such as level of the mosaicism, size and gene content. There are genomic regions which can be present in three or more copies withouth causing harm, whereas other regions are dose-sensitive. If no genetically relevant material can be detected, in several cases this means that the sSMC will have no direct clinical impact on the phenotype of its carrier. Most critical are the prenatal sSMC cases. The risk depends on a number of factors, including ultrasound findings, whether the SMC is familial and if it is associated with a known syndrome. For some cases, the chromosomal abnormality led to an even more imbalanced, and subsequently unviable, situation in the potential offspring than that present in the sSMC carriers themselves. Thus, the correct identification and characterization of sSMCs has a major impact on the families.

Background Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. Methods We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. Results We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. Conclusion Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

Pallister-Killian syndrome (PKS-#OMIM601803) is a multisystem developmental disorder typically due to the presence of an aneuploidy cell line, consisting of a supernumerary tetrasomic chromosomal marker (SCM) arisen from the short arm of chromosome 12 (12p isochromosome). The clinical phenotype, which is strictly related to the percentage and tissue distribution of aneuploid cells, is characterized by craniofacial dysmorphisms, pigmentary skin anomalies, limb shortening, congenital heart defects, diaphragmatic hernia, hypotonia, intellectual disability, and epilepsy. We report on a 4 year-old girl harboring a 12p partial isochromosome, involving the PKS critical region, affecting about 70% of circulating lymphocytes, urine, and saliva cells and fibroblast from a hyperpigmented skin spot, and 100% of fibroblasts from a hypopigmented skin spot. Interestingly, despite the high proportion of affected cells this patient did not present with PKS, and a pattern of linear and patchy pigmentary mosaicism was the sole clinical manifestation. The present observation suggests that partial 12p SCM can also result in mild phenotypes, and its prevalence in the human population could have been underestimated. Accurate dermatologic evaluation could be a major handle for genetic testing.

Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they cannot be identified or characterized unambiguously by conventional cytogenetics alone. On the other hand, and perhaps more importantly in prenatal settings, there is a challenging situation for counseling how to predict the risk for an abnormal phenotype, especially in cases with a de novo sSMC. Here we report on the prenatal diagnosis of a mosaic tetrasomy 18p due to presence of an sSMC in a fetus without abnormal sonographic signs. For a 26-year-old, gravida 2 (para 1) amniocentesis was done due to consanguineous marriage and concern for Down syndrome, based on borderline risk assessment. Parental karyotypes were normal, indicating a de novo chromosome aberration of the fetus. FISH analysis as well as molecular karyotyping identified the sSMC as an i(18)(pter->q10:q10->pter), compatible with tetrasomy for the mentioned region. Cordocentesis was done due to normal sonography and the results from amniocentesis were confirmed. The parents opted for pregnancy termination and post mortem examination now noted, low anterior hairline, large philtrum, low-set posteriorly rotated malformed ears with prominent antihelix, lower limbs joint contracture and digital anomalies, including long and narrow toes with clinodactyly of the 1st and 5th toes and postaxial polydactyly of one hand. De novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal. This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result and the suitability of a cordocentesis in order to better predicting the pregnancy outcome and parental counseling.

The Xp22.31 duplication is a copy number variant which is challenging to categorize as pathogenic or benign. There is an increasing number of patients with the duplication and a neurobehavioral phenotype, but the duplication is almost always inherited from a parent, who in some cases is phenotypically normal. Also, the duplication is detected in the general population, though in a smaller percentage than in clinically ascertained populations. The Xp22.31 triplication has only been identified in 3 individuals of a large cohort of developmental delay cases but never in the control cohorts or general population. We report a severely affected female with an Xp22.31 tetrasomy, inherited from duplications identified in both phenotypically normal parents. Although our study has limitations, it suggests that the Xp22.31 triplication seems to be more penetrant than the duplication and is associated with a neurological phenotype.

Objective Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). Clinically, PKS is characterized by several systemic abnormalities, such as intellectual impairment, hearing loss, epilepsy, hypotonia, craniofacial dysmorphism, pigmentary skin anomalies, epilepsy, and a variety of congenital malformations. Prenatally, PKS can be suspected in the presence of ultrasound anomalies: diaphragmatic hernia, rhizomelic micromelia, hydrops fetalis, fetal overweight, ventriculomegaly in the central nervous system, congenital heart defects, or absent visualization of the stomach. In all these cases, a detailed genetic study is required. PKS is diagnosed by prenatal genetic analysis through chorionic villus sampling, genetic amniocentesis, and cordocentesis. Case Report We report two cases of PKS with prenatal diagnosis of isochromosome 12p made by cytogenetic studies. The first case is of a 36-year-old pregnant woman who underwent genetic chorionic villus sampling at 13 th weeks of gestation after 1 st trimester prenatal ultrasound revealed clinical features of PKS: flat nasal bridge and fetal hydrops. The second case is of a 32-year-old pregnant woman with genetic amniocentesis at 17 th weeks of gestation that showed mos46,XX[21]/47,XX,+i(12p) associated to PKS. Conclusion New molecular cytogenetic techniques array comparative genomic hybridization and fluorescence in-situ hybridization in association with conventional karyotype are pivotal innovative tools to search for chromosomic anomalies and for a complete prenatal diagnosis, especially in cases such as PKS where array comparative genomic hybridization analysis alone could not show mosaicism of i(12p).

Cholangiocarcinoma (CCA) is a leading cause of death in patients with primary sclerosing cholangitis (PSC). Biliary polysomy detected by fluorescence in situ hybridization (FISH) helps to identify patients with early CCA, but not all PSC patients with polysomy develop CCA. Here, we examined the features and clinical outcomes of PSC patients with serial versus isolated polysomy.All patients with PSC who underwent ≥1 endoscopic retrograde cholangiography (ERC) with FISH testing at Mayo Clinic, Rochester from 2008-2011 were identified. Patients diagnosed with CCA at the time of initial polysomy were excluded. Serial polysomy was defined as polysomy on ≥2 ERCs; isolated polysomy was defined as polysomy once followed by all nonpolysomy results. The primary outcome was the diagnosis of CCA.Twenty-seven patients with polysomy and ≥1 subsequent ERC with FISH were identified. Of these, 11 (40.7%) had serial polysomy and 16 (59.3%) had isolated polysomy. CCA was more likely to be diagnosed in patients with serial versus isolated polysomy (36.4% vs. 6.3%; p = .046). Overall, four patients (36.4%) with serial polysomy and three (18.8%) with isolated polysomy underwent liver transplantation (LT), with time to LT being significantly shorter for the former (14.0 vs. 65.4 months; p = .0003).Biliary polysomy reverted in ≥50% of patients with PSC; this group appears to be at decreased risk of CCA compared to those with serial polysomy. Nevertheless, both groups should be followed closely, and those with serial polysomy may benefit from early LT evaluation.

Key Clinical Message Tetrasomy X is a rare chromosomal anomaly in which sleep disorders have not been previously reported. We report on one patient with tetrasomy X and hypersomnia successfully treated with psychostimulant therapy. Sleep disorders are rarely reported in chromosomal anomalies. Clinicians should screen patients for sleep disorders and manage them appropriately.

Pallister–Killian syndrome (PKS) is a rare sporadic genetic disorder caused by a mosaic tetrasomy of chromosome 12p, which mainly manifests with craniofacial dysmorphism, intellectual disability (ID), auditory disturbance, epilepsy, and a variety of congenital malformations. The diagnosis of PKS can be complicated due to the phenotypic variation, and an overlap with other syndromes makes the molecular cytogenetic test necessary for a correct diagnosis. We identified two unrelated patients with typical facial features of PKS, including bitemporal alopecia, hypertelorism, and abnormal ears. Furthermore, the two patients had pigmentary skin anomalies, broad and short hands and fingers, and hypotonia. However, they differed in the degree of ID and ophthalmological findings. Patient 1 showed profound ID and poor macular function, whereas patient 2 had moderate ID and normal fundus. Mosaic tetrasomy of chromosome 12p was found in 40 and 25% of the cells of patients 1 and 2, respectively, by fluorescent in situ hybridization of cultured skin fibroblasts. The higher percentage of mosaic cells with tetrasomy 12p found in patient 1 may explain the severe phenotype. This report expands the clinical manifestations of PKS and highlights the variable expressivity of clinical features in relation to the cytogenetics findings.

Background Pallister–Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. Methods Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. Results Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. Conclusion Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.

Введение. Тетрасомия дистального района длинного плеча хромосомы 15 является довольно редким событием. В электронной базе данных по сверхчисленным маркерным хромосомам имеются сведения о 24 зарегистрированных случаях с инвертированной дупликацией дистального района длинного плеча хромосомы 15. Частичная тетрасомия 15q может наблюдаться вследствие появления сверхчисленной анальфоидной маркерной хромосомы, состоящей из инвертированной дупликации дистальной части длинного плеча хромосомы 15. Представлен случай мозаичной тетрасомии 15q25.3-qter, у пациента со множественными признаками дизэмбриогенеза. Цель. Молекулярно-цитогенетическая диагностика мозаичного случая инвертированной дупликации 15q25.3qter у пациента с множественными врожденными аномалиями развития и обзор аналогичных случаев. Методы. Для идентификации малой сверхчисленной маркерной хромосомы и определения уровня мозаицизма использовали комплексную молекулярно-цитогенетическую диагностику, включающую хромосомный микроматричный анализ и FISH-исследование. Результаты. При стандартном цитогенетическом исследовании обнаружена сверхчисленная маркерная хромосома в мозаичном состоянии: 47,ХХ,mar8/46,XX23. Для идентификации геномного дисбаланса использовали хромосомный микроматричный анализ, выявивший дупликацию участка длинного плеча хромосомы 15 размером 16,4 млн п.н. FISH-исследование позволило установить, что сверхчисленная маркерная хромосома представлена инвертированной дупликацией района q25.3qter хромосомы 15 с неоцентромерой, и помогло уточнить уровень мозаицизма, который составил 35. Заключение. Идентификация структуры и происхождения сверхчисленных маркерных хромосом у пациентов с множественными врожденными аномалиями развития является важной задачей цитогенетической лаборатории. Современные молекулярно-цитогенетические методы диагностики хромосомных аномалий позволяют выявить и охарактеризовать любой случай неоцентромерной формации., Introduction: Tetrasomy for the distal chromosome 15q is rare. Only 24 cases have been described in the literature to date. Tetrasomy for the distal portion of chromosome 15q can be due to a supernumerary analphoid marker chromosome consisting of an inverted duplication of the distal long arm of chromosome 15. We report on a molecular cytogenetic diagnosis of mosaic tetrasomy 15q25.3-qter in a patient with multiple congenital anomalies. Aim: Molecular cytogenetic diagnosis of mosaic case with inverted duplication for the distal portion of 15q25.3qter in a patient with multiple congenital anomalies and review of the literature. Methods: The case of mosaic supernumerary marker chromosome was characterized by GTG-banding, chromosomal microarray analysis and FISH diagnosis. Results: The chromosome analysis of a child revealed a supernumerary marker chromosome in mosaicism: 47,ХХ,mar8/46,XX23. Chromosomal microarray analysis detected a copy gain of 16.4 Mb from the distal long arm of chromosome 15. Further FISH analysis showed an inverted duplication of distal long arm of chromosome 15 with neocentromere. Conclusion: Identification of structure and origin supernumerical marker chromosomes at patients with multiple congenital anomalies is an important problem of cytogenetic diagnostics. Modern molecular -cytogenetic diagnostic methods of chromosomal anomalies allow identifying and characterizing any case of neocentromeres., №7 (2020)

A parental diagnosis was performed for an unborn foetus of a healthy couple, who was due for ultrasound detection of multiple malformations and abnormal amniotic fluid karyotypes. For an accurate diagnosis, routine G-banding analysis and next generation sequencing (NGS) were carried out. Finally, conventional cytogenetic analysis suggested that the foetus had a karyotype of47,XX,+mar[52]/46,XN, meanwhile NGS also revealed a partial tetrasomy of 27.84Mb from 4q26-q31.21 (117,385,735-145,225,759), and G-banding analysis excluded the couple to have carried the 4q26-q31.21 duplication. We have identified a