Molecular Cytogenetics最新文献

It is hard to believe that all the cells of a human brain share identical genomes. Indeed, single cell genetic studies have demonstrated intercellular genomic variability in the normal and diseased brain. Moreover, there is a growing amount of evidence on the contribution of somatic mosaicism (the presence of genetically different cell populations in the same individual/tissue) to the etiology of brain diseases. However, brain-specific genomic variations are generally overlooked during the research of genetic defects associated with a brain disease. Accordingly, a review of brain-specific somatic mosaicism in disease context seems to be required. Here, we overview gene mutations, copy number variations and chromosome abnormalities (aneuploidy, deletions, duplications and supernumerary rearranged chromosomes) detected in the neural/neuronal cells of the diseased brain. Additionally, chromosome instability in non-cancerous brain diseases is addressed. Finally, theoretical analysis of possible mechanisms for neurodevelopmental and neurodegenerative disorders indicates that a genetic background for formation of somatic (chromosomal) mosaicism in the brain is likely to exist. In total, somatic mosaicism affecting the central nervous system seems to be a mechanism of brain diseases.

Background: The history of comparative chromosome mapping is briefly reviewed, with discussion about the problem that occurs in chromosome painting when size heteromorphisms between homologues cause contamination in chromosomes sorted by flow cytometry that are used in the preparation of chromosome-specific DNA probes.

Main body: As an example, we show in the alpaca (Vicagna pacos) that sequencing of contaminated chromosome sorts can reveal chromosome homologies from alignment with human and mouse genome reference sequences. The procedure identifies syntenic blocks of DNA separated in the human karyotype that are associated in the closely related alpaca and dromedary (Camelus dromedarius) karyotypes. This example provides proof of principal for the validity of the method for comparative chromosome mapping.

Conclusion: It is suggested that the approach presented here may have application in the construction of comparative chromosome maps between distantly related taxa, such as monotremes and mammals.

Background: Acute myeloid leukemia (AML) is a diverse disease characterized by the expansion of blasts of myeloid lineage. Cytogenetic testing is the cornerstone for risk stratification of AML patients. Geographical and environmental factors may play a very important role in the development of leukemia and several differences in genetic profile may be seen among different ethnicities. In our study, we evaluated cytogenetic findings of adult AML patients in South Egypt.

Methods: Cytogenetic testing (karyotyping and M-FISH) was performed for 120 adult patients with AML. Twenty metaphases were analyzed for each patient.

Results: In our study, the median age of AML patients was 36.5 years, with an age range between 18 and 86 years. 56.7% of patients had normal karyotypes and 43.3% of patients had clonal cytogenetic abnormalities. t (15;17) was the most detected structural abnormality, and + 8 was the most detected numerical abnormality. Regarding cytogenetic risk stratification, 65% of patients were in the intermediate-risk category.

Conclusion: The cytogenetic profile of AML patients in our locality showed some differences and some similarities with cytogenetic profiles in different Arab, Asian and Western countries. Further studies are needed using advanced techniques such as next-generation sequencing and optical genome mapping to elucidate more ethnic and geographic genetic heterogeneity among different countries.

Background: Corpus callosum malformations (CCM) represent one of the most common congenital cerebral malformations with a prevalence of around one for 4000 births. There have been at least 230 reports in the literature concerning 1q43q44 deletions of varying sizes discovered using chromosomal microarrays. This disorder is distinguished by global developmental delay, seizures, hypotonia, corpus callosum defects, and significant craniofacial dysmorphism. In this study, we present a molecular cytogenetic analysis of 2 Tunisian patients with corpus callosum malformations. Patient 1 was a boy of 3 years old who presented psychomotor retardation, microcephaly, behavioral problems, interventricular septal defect, moderate pulmonary stenosis, hypospadias, and total CCA associated with delayed encephalic myelination. Patient 2 was a boy of 9 months. He presented a facial dysmorphia, a psychomotor retardation, an axial hypotonia, a quadri pyramidal syndrome, a micropenis, and HCC associated with decreased volume of the periventricular white matter. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used.

Results: Array CGH analysis reveals that patient 1 had the greater deletion size (11,7 Mb) at 1q43. The same region harbors a 2,7 Mb deletion in patient 2. Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. In both patients, the commonly deleted region includes six genes: PLD5, AKT3, ZNF238, HNRNPU, SDCCAG8 and CEP170. Based on the role of the ZNF238 gene in neuronal proliferation, migration, and cortex development, we hypothesized that the common deletion of ZNF238 in both patients seems to be the most responsible for corpus callosum malformations. Its absence may directly cause CCM. In addition, due to their high expression in the brain, PLD5 and FMN2 could modulate in the CCM phenotype.

Conclusion: Our findings support and improve the complex genotype-phenotype correlations previously reported in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of several genes related to this pathology.

Background: Complex chromosomal rearrangements (CCRs) are rare chromosomal structural variations, containing a variety of rearrangements such as translocation, inversion and/or insertion. With the development of cytogenetic and molecular genetic techniques, some chromosomal rearrangements that were initially considered to be simple reciprocal translocations in the past might eventually involve more complex chromosomal rearrangements.

Case presentation: In this case, a pregnant woman, who had a spontaneous abortion last year, had abnormal prenatal test results again in the second pregnancy. Applying a combination of genetic methods including karyotype analysis, chromosomal microarray analysis, fluorescence in situ hybridization and optical genome mapping confirmed that the pregnant woman was a carrier of a CCR involving three chromosomes and four breakpoints, and the CCR was paternal-origin. Her first and second pregnancy abnormalities were caused by chromosomal microdeletions and microduplications due to the malsegregations of the derivative chromosomes.

Conclusions: We presented a rare familial CCR involving three chromosomes and four breakpoints. This study provided precise and detailed information for the subsequent reproductive decision-making and genetic counselling of the patient.

Background: Hemophilia A is considered one of the most common severe hereditary disorders. It is an X-linked recessive disease caused by a deficiency or lack of function of the blood clotting factor VIII. Klinefelter syndrome is a genetic disorder that affects male individuals due to one or more extra X chromosomes, present in all cells or with mosaicism. The aneuploidy is due to either mitotic or meiotic chromosome non-disjunction. Chromosomal translocations are a group of genome abnormalities in which a region or regions of a chromosome break and are transferred to a nonhomologous chromosome or a new location in the same chromosome.

Case presentation: Our subject was born in Ecuador at 36 weeks of gestation by vaginal delivery. At 3 months old, the Factor VIII activity measure showed a 23.7% activity indicating a diagnosis of mild hemophilia A. At 1 year old, the karyotype showed an extra X chromosome, consistent with a diagnosis of Klinefelter syndrome, and a translocation between the long arms of chromosomes 1 and 19, at positions q25 and q13, respectively.

Conclusions: Klinefelter syndrome and hemophilia are a rare combination. In the present case report, the subject presents both, meaning that he has inherited one X chromosome from the father and one X chromosome from the mother. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested. Additionally, the proband presents a translocation with the karyotype 47,XXY,t(1;19)(q25;q13). No similar report with phenotypic consequences of the translocation was found. The present report highlights the importance of a correct diagnosis, based not only on the clinical manifestations of a disease but also on its genetic aspects, identifying the value of integrated diagnostics. The subject presents three different genetic alterations, Klinefelter syndrome, hemophilia A, and a 1;19 chromosomal translocation.

Background: Copy number variants are a substantial source of pathogenic or normal genome variations. Chromosomal imbalances of several megabasepair are normally harmful for the affected person. Still, rarely reported are so-called "unbalanced chromosome abnormalities" (UBCAs), which are either losses or gains or equally large genomic regions, but the carrier is only minimally clinically affected even no clinically affected. The knowledge of such UBCAs is imperative also in noninvasive prenatal testing (NIPT) or chromosomal microarray analysis.

Case presentation: A paternally inherited dup(18)(q11.1q11.2) was identified in a over two generations in a Chinese family. The affected region encompasses 25 genes, among which GATA6 is expressed in fetal endothelial cells and mesodermal cells. GATA6 duplications and /or mutations have been seen in cases with congenital heart disease but also non-affected individuals, suggesting incomplete penetrance and variable expressivity.

Conclusions: Duplications in the region of chromosome 18q11 have been rare reported previously in clinically healthy persons. Here a further family with an UBCA in 18q11 is added to the literature, suggesting a careful genetic counselling in prenatal diagnosis.

Background: So called cell-free fetal DNA (cffDNA) in the maternal plasma, which is derived from placenta, is widely used to screen fetal aneuploidies, including trisomy 21, 18, 13 and sex chromosomes. Here we reported a case of trisomy 8 mosaicism (T8M), which was initially identified via cffDNA screening in noninvasive prenatal testing (NIPT).

Methods: A 35-year-old woman received cffDNA screening at 17th week of gestation. Amniocentesis was performed subsequently, and karyotyping, single-nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs™) were used to determine fetal chromosome content. Interphase fluorescence in situ hybridization (FISH) was applied to determine the copy number of chromosome 8.

Results: An enhanced risk for fetal trisomy 8 was identified by cffDNA screening in the studied pregnant woman. After amniocentesis trisomy 8 was found in 1 of 73 metaphases. SNP-array on DNA derived from cultured amniocytes and neonatal cord blood cells suggested the presence of T8M. Interphase FISH on native neonatal cord blood cells confirmed T8M with a percentage of 10%. The Bobs™ fluorescence data also suggested that 8q23-8q24 was amplified.

Conclusions: The current study shows that NIPT is suited to provide hints on rare autosomal trisomies, which have to be further validated and confirmed by other approaches.

Complex chromosomal rearrangements (CCR) are rare chromosomal structural abnormalities. The chromosomal structural variants in CCR carriers are one of the factors contributing to a history of adverse pregnancy and childbirth. In this study, we report a patient with a history of adverse pregnancy and childbirth who exhibited complex balanced chromosomal translocations. The female patient was phenotypically and intellectually normal; in her first pregnancy, the embryo was damaged, and a histological examination of the chromosomes of the embryos revealed a deletion of approximately 4.66 Mb at 1p32.3p32.2, a duplication of approximately 1.02 Mb at 1p22.2p22.1, a duplication of approximately 1.46 Mb at 6q27 and a deletion of approximately 7.78 Mb at 9p24.3p24.1. Chromosomal examinations of the patient revealed the karyotype to be 46,XX,(1;9)(p32; p34). In the second pregnancy, the foetus was diagnosed prenatally with three or more positive ultrasound soft indicators. The patient's karyotype was re-examined and further confirmed by fluorescence in situ hybridisation as 46,XX,t(1;9;6)(p31;p22;q27), revealing this patient was a carrier of complex balanced chromosomal translocations. Carriers of CCR have a higher risk of spontaneous abortion, and genetic counselling clinicians should consider the karyotype analyses of such patients in clinical practice and recheck their chromosomes if necessary.