Molecular Cytogenetics最新文献

Background: Non-invasive prenatal testing (NIPT) has had an incomparable triumph in prenatal diagnostics in the last decade. Over 1400 research articles have been published, predominantly praising the advantages of this test.

Methods: The present study identified among the 1400 papers 24 original and one review paper, which were suited to re-evaluate the efficacy of > 750,000 published NIPT-results. Special attention was given to false-positive and false-negative result-rates. Those were discussed under different aspects-mainly from a patient-perspective.

Results: A 27: 1 rate of false-positive compared to false-negative NIPT results was found. Besides, according to all reported, real-positive, chromosomally aberrant NIPT cases, 90% of those would have been aborted spontaneously before birth. These findings are here discussed under aspects like (i) How efficient is NIPT compared to first trimester screening? (ii) What are the differences in expectations towards NIPT from specialists and the public? and (iii) There should also be children born suffering from not by NIPT tested chromosomal aberrations; why are those never reported in all available NIPT studies?

Conclusions: Even though much research has been published on NIPT, unbiased figures concerning NIPT and first trimester screening efficacy are yet not available. While false positive rates of different NIPT tests maybe halfway accurate, reported false-negative rates are most likely too low. The latter is as NIPT-cases with negative results for tested conditions are yet not in detail followed up for cases with other genetic or teratogenic caused disorders. This promotes an image in public, that NIPT is suited to replace all invasive tests, and also to solve the problem of inborn errors in humans, if not now then in near future. Overall, it is worth discussing the usefulness of NIPT in practical clinical application. Particularly, asking for unbiased figures concerning the efficacy of first trimester-screening compared to NIPT, and for really comprehensive data on false-positive and false-negative NIPT results.

Background: Unbalanced chromosome abnormalities (UBCA) are either gains or losses or large genomic regions, but the affected person is not or only minimally clinically affected. Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. CNVs and UBCA identified in prenatal cases need careful considerations and correct interpretation if those are harmless or harmful variants from the norm.

Case presentation: A 25-year-old, gravida 1, para 0, woman underwent amniocentesis at 18 weeks of gestation because the noninvasive prenatal testing (NIPT) results revealed a 6.8 Mb duplication from 2q11.1 to 2q11.2. Chromosomal microarray analysis (CMA) was performed on uncultured amniocytes. GTG-banding karyotype analysis on cultured amniocytes was performed.

Results: Chromosomal GTG-banding of the cultured amniocytes revealed a karyotype of 46,XX. CMA detected a 6.8-Mb chromosomal duplication in the region of 2q11.1q11.2 (arr[GRCh37] 2q11.1q11.2(95,327,873_102,088,148)x3).

Conclusion: Chromosomal microdeletions and microduplications are difficult to detect by conventional cytogenetics, combination of prenatal ultrasound, karyotype analysis, NIPT, CMA and genetic counseling is helpful for the prenatal diagnosis of UBCA and chromosomal microdeletions/microduplications.

Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.

Background: The mosaic forms and clinical phenotypes of fetuses with isochromosome Y are difficult to predict. Therefore, we summarized the cases of nine fetuses with isochromosome Y identified in prenatal diagnosis with a combination of molecular cytogenetic techniques, providing clinical evidence for prenatal genetic counseling.

Methods: The prenatal diagnosis and pregnancy outcomes of nine fetuses with isochromosome Y were obtained by a  retrospective analysis. Isochromosome Y was identified prenatally by different approaches, such as conventional karyotyping, chromosomal microarray analysis (CMA), quantitative fluorescent polymerase chain reaction (QF-PCR) and fluorescence in situ hybridization (FISH).

Results: Seven idic(Y) fetuses and two i(Y) fetuses were identified. One fetus was complete for i(Y)(p10), and the rest with 45,X had mosaic forms. A break and fusion locus was identified in Yp11.3 in one fetus, in Yq11.22 in six fetuses and in Yp10 in two fetuses. The CMA results suggested that different deletions and duplications were found on the Y chromosome. The deletion fragments ranged from 4.7 Mb to the entire Y chromosome, and the duplication fragments ranged from 10.4 to 18.0 Mb. QF-PCR analysis suggested that the AZF region was intact in one fetus, four fetuses had AZFb+c+d deletion, one fetus had AZFa+b+c+d deletion, and one fetus had AZFc+d deletion. Finally, four healthy male neonates were delivered successfully, but the parents of the remaining five fetuses, including three healthy and two unhealthy fetuses, chose to terminate their pregnancies.

Conclusion: The fetus and neonate phenotype of prenatally detected isochromosome Y usually is that of a normally developed male, ascertained in the absence of other indicators of a fetal structural anomaly. Our study provides clinical reference materials for risk assessment and permits better prenatally counseling and preparation of parents facing the birth of isochromosome Y fetuses.

Background: Partial trisomy 13q is a less common chromosomal abnormality with a great clinical variability, among them, isolated partial trisomy 13q is extremely rare. Here, we report two new unrelated cases of partial trisomy 13q in Chinese families aiming to emphasize the genotype-phenotype correlation in partial trisomy 13q.

Methods: Enrolled in this study were two unrelated cases of partial 13q trisomy from two families in Quanzhou region South China. Karyotpe and single-nucleotide polymorphism (SNP) array analysis were employed to identify chromosome abnormalities and copy number variants in the families.

Results: A 72.9-Mb duplication in 13q14.11q34 region was identified using SNP array analysis in Patient 1 with an intellectual disability, developmental delay, seizures, gastric perforation, and other congenital malformations from a family with paternal inv(13)(p12q14.1). SNP array detection in Patient 2 revealed a 92.4-Mb duplication in 13q12.11q34 region combined with an 8.4-Mb deletion in Xq27.3q28 region with intellectual disability, developmental delay, cleft palate, and duplication of the cervix and the vagina. No chromosomal abnormality was elicited from the parents of Patient 2.

Conclusions: In this study, we presented two new unrelated cases of partial trisomy 13q with variable features in Chinese population, which may enrich the spectrum of the phenotypes partial trisomy 13q and further confirm the genotype-phenotype correlation.

Background: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized.

Case presentation: Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks.

Conclusions: Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes.

Objective: Since 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion, with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool are lacking. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations in order to inform pre- and post-test counseling, pre/perinatal decision making, and medical risk assessment/management.

Methods: This retrospective study included women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing, including karyotyping, chromosomal microarray analysis (CMA) were performed. Positive predictive values (PPVs) were calculated.

Results: In total, 468 women were recruited. The PPVs for trisomies 21, 18, and 13 were 86.1%, 57.8%, and 25.0%, respectively. The PPVs for rare chromosomal abnormalities (RCAs) and copy number variants (CNVs) were 17.0% and 40.4%, respectively. The detection of sex chromosomal aneuploidies (SCAs) had a PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY, and 62.5% for 47,XYY. The high-risk groups had a significant increase in the number of true positive cases compared to the low- and moderate-risk groups.

Conclusions: T13, monosomy X, and RCA were associated with lower PPVs. The improvement of cell-free fetal DNA screening technology and continued monitoring of its performance are important.

Background: Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion has been previously associated with developmental delay, mental retardation, epilepsy, autism, schizophrenia and congenital heart defects. The literature on this microdeletion is extensive and confusing, which is a challenge for genetic counselling.

Case presentation: We have performed prenatal diagnosis and genetic counseling of a paternally inherited 15q11.2 microdeletion. In this family, father with normal phenotype and fetus with abnormal phenotype have the same microdeletion.

Conclusion: Chromosomal microdeletions and microduplications are difficult to detect by conventional cytogenetics, combination of prenatal ultrasound, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

Background: There are a few literature reports of prenatal ultrasound manifestations of Williams-Beuren syndrome. We aimed to explore the prenatal diagnosis of Williams-Beuren syndrome by ultrasound and chromosomal microarray analysis and describe the prenatal ultrasound performance of this syndrome.

Methods: In this retrospective study, we reported eight cases of Williams-Beuren syndrome diagnosed at our prenatal diagnostic center from 2016 to 2021. We systematically reviewed clinical data from these cases, including indications for invasive testing, sonographic findings, QF-PCR results, chromosomal microarray analysis results, and pregnancy outcomes.

Results: In this study, the common ultrasound features were ventricular septal defect (37.5%), intrauterine growth retardation (25%), and aortic coarctation (25%). Moreover, all patients were found to have a common deletion in the Williams-Beuren syndrome chromosome region at the 7q11.23 locus, which contained the elastin gene. Deletion sizes ranged from 1.42 to 2.07 Mb. Seven parents asked for termination of pregnancy, and one patient was lost to follow-up.

Conclusions: This study is the most extensive prenatal study using chromosomal microarray analysis technology for detailed molecular analysis of Williams-Beuren syndrome cases. We reported three cases combined with first-reported ultrasound manifestations. Case 1 was concomitant with multicystic dysplastic kidney and duodenal atresia combined with case 3. Notably, case 4 was combined with multiple cardiovascular malformations: Tetralogy of Fallot, right aortic arch, and supravalvar aortic stenosis. These manifestations expand the intrauterine ultrasound phenotype of Williams-Beuren syndrome in previous literature reports.

Background: Tetrasomy 18p syndrome is a rare chromosomal disorder that is caused by the presence of isochromosome 18p. Most tetrasomy 18p cases are de novo cases and maternal origin of trisomy 18p is a rare condition. At present, only four cases of maternal origin have been reported in worldwide.This is the fifth case of tetrasomy 18p originating from maternal trisomy 18p. The mother of the fetus studied had no apparent disease phenotype.

Case presentation: The current case report is to describe a fetus with confirmed 18p tetrasomy as detected by karyotyping and Single Nucleotide Polymorphism array (SNP array) analysis. However, the fetus showed normal phenotypic features that were observed using ultrasound scans. The mother and maternal grandfather were phenotypically normal and healthy; however, they were diagnosed with trisomy 18p, which was confirmed by conventional karyotyping and SNP array.

Conclusions: We report a case of 18p tetrasomy in a fetus whose mother and grandfather had 18p trisomy. The mother and grandfather were phenotypically normal. Our case report findings provide an important reference for the genetic counseling of trisomy 18p in the future.