Molecular Cytogenetics最新文献

Over 90% of patients with acute promyelocytic leukemia (APL) harbor the typical translocation characterized by the dual fusion of PML::RARA and RARA::PML transcripts. Here, we report a case with a single fusion of PML::RARA formed on der(17), without the RARA::PML fusion, and the patient responded well to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. To our knowledge, this represents only the fourth reported case of this type. Our findings indicate that the PML::RARA fusion is the primary driver of APL leukemogenesis and the main therapeutic target for ATRA and ATO, suggesting that the RARA::PML transcript may not be essential for APL development.

Background: X-linked disorders caused by skewed X chromosome inactivation (XCI) result in phenotypic heterogeneity, which is rarely reported. XCI testing is not widely used in clinical cases, making risk assessment for carriers of X-linked unbalanced structural abnormalities challenging.

Case presentation: We present genetic data from an asymptomatic female with a de novo 6.31 Mb deletion on Xp11.23-p11.22, identified through CMA-array analysis. The deletion includes 101 OMIM genes, 11 haplo-insufficient (HI) genes, and 4 escape genes. An androgen receptor (AR) methylation assay showed a 100% skewed XCI pattern silencing the abnormal X-chromosome. RNA-seq analysis revealed up-regulation of escape genes within the deletion at the transcriptional level. The absence of a severe clinical phenotype, aside from infertility, in this female was most likely attributed to the extremely skewed XCI and the compensatory up-regulation of XCI escape genes.

Conclusions: Our data indicate that XCI can modify the phenotype in female carriers of heterozygous X-linked deletion and provide valuable information about the analysis of XCI pattern in risk assessment of this kind cases, especially precious fetuses.

Background: Prader-Willi Syndrome (PWS) is a complicated genetic disorder demonstrating a variety of clinical phenotypes. Using molecular cytogenetics approaches to detect the deletions of the paternal 15q11-q13 region and maternal uniparental disomy of chromosome 15 plays an important role in the prenatal diagnosis of PWS.

Case presentation: A pregnant woman with advanced maternal age underwent amniocentesis. The amniotic fluid was subjected to karyotyping and chromosomal microarray analysis. A marker without autosomal material and loss of heterozygosity (LOH) of 15q14-q23 were found in the fetus. The LOH was consistent with maternal uniparental isodisomy (UPD) and the marker was inherited from the father. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) found increased methylation in the fetal 15q11.2-q13 region and fluorescence in situ hybridization confirmed the marker was not originated from chromosome 15.

Conclusion: We presented a rare PWS case showing maternal UPD of chromosome 15 with concurrent paternal marker chromosome in the prenatal setting.

Objective: This study aimed to investigate the role of pathogenic copy number variations (CNVs) in neurodevelopmental impairments among children with corpus callosum abnormalities (CCAs). We focused primarily on SLC6A3 associated mechanisms and aimed to delineate genotype-phenotype correlations in our cases.

Methods: From January 2021 to July 2023, 13 children with MRI-confirmed CCAs underwent chromosomal microarray analysis (CMA) for CNV detection. We performed bioinformatic analyses (Gene Ontology, STRING network) to identify neurodevelopmental genes within pathogenic CNVs, and clinical follow up assessed neurobehavioral outcomes.

Results: We identified pathogenic CNVs in 3/13 cases (23.08%). Specifically, Case 8 harbored a 43.05-Mb duplication (5p15.33p12) encompassing SLC6A3, a dopamine transporter gene linked to synaptic signaling. Interaction network analysis suggested that SLC6A3 was the most interconnected gene, providing evidence of its role in CCAs. Clinically, 84.6% of cases (11/13) exhibited psychomotor delay, while 15.4% of cases (2/13) developed seizure. Notably, we observed hearing impairment and psychomotor developmental delay in Case 8 with a SLC6A3 duplication, further suggesting dopaminergic dysregulation in callosal connectivity.

Conclusion: Our study suggests that SLC6A3 may represent a potential contributor to neurodevelopmental impairments in CCAs. Further, CMA-based CNV screening is critical for early intervention in high-risk children. These findings bridge genetic etiology with clinical phenotypes and offer insights into future targeted therapeutic strategies.

Introduction: Embryonic chromosomal abnormalities are the major cause of miscarriage. As a relatively novel genetic screening technology, high-throughput ligation-dependent probe amplification combined with short tandem repeat analysis (HLPA + STR) demonstrates significant clinical advantages, including shorter turnaround time, user-friendly technical workflows, and superior cost-effectiveness. The purpose of this study is to evaluate the frequency and characteristics of fetal chromosomal abnormalities using HLPA + STR in early pregnancy loss (EPL).

Methods: A retrospective analysis was conducted on women who experienced EPL and underwent HLPA + STR. Group differences were compared using χ2 or Fisher's exact test, and multivariate logistic regression analysis was performed to examine the correlation between the fetal cytogenetic results and maternal age, gestational age, and history of miscarriage.

Results: In total, 820 (61.75%) cases were detected to be chromosomal abnormalities, including 748 (91.22%) had numerical abnormalities, 59 (7.19%) had structural abnormalities, and 13 (1.59%) had chromosome mosaicism. The most frequent chromosomal abnormality was autosomal trisomy, of which trisomy (T) 16 was the most common, followed by sex chromosome monosomy and triploid. The incidence of fetal chromosomal abnormalities was significantly higher advanced maternal age (AMA) than in non-advanced maternal age (non-AMA) (p < 0.001). The AMA had a 1.93 times higher risk of fetal chromosomal abnormalities compared to the non-AMA (odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.39-2.68; p < 0.001). The risk of fetal chromosomal abnormalities in fetuses with a gestational age > 8 weeks was found to be 1.34 times higher compared to those with a gestational age ≤ 8 weeks (OR, 1.34; 95% CI, 1.07-1.69; p = 0.012). No statistically significant variation in fetal chromosomal abnormalities was observed in the history of miscarriage (p > 0.05).

Conclusion: In conclusion, our results show that HLPA + STR is an effective strategy for cytogenetic analysis of EPL. In addition, Multivariate analysis identified advanced maternal age and gestational age are independent risk factors for fetal cytogenetic results in EPL, but not related to the history of miscarriage. Therefore, we recommend HLPA + STR as the first-tier screening tool for genetic evaluation in EPL. However, the results of complex abnormalities need to be combined with other techniques.

We report on a consanguineous family with two infertile sisters with oocyte arrest and prematurely condensed sperm chromosomes. A genome-wide linkage scan and exome sequencing revealed a homozygous variant in the gene for the thyroid receptor interacting protein 13 (TRIP13), c.518G˃A (p.Arg173Gln), affecting an evolutionary highly conserved amino acid within an ATP binding motif. Just recently, compound heterozygosity for this variant was described in a Chinese proband as pathogenic, confirming that the homozygous mutation is causative for the oocyte arrest. The TRIP13 gene and the orthologous yeast pch2 gene are, amongst others, involved in a meiotic checkpoint control. This checkpoint defect is obviously responsible for the premature condensation of the sperm chromosomes. TRIP13 and pch2 are involved in meiotic recombination. To exclude that it is involved in reciprocal somatic exchanges, we analyzed the rate of sister chromatid exchanges (SCEs) in the proband´s lymphoblastoid cells. Obviously, TRIP13 is not involved in this type of somatic recombination. Moreover, we tested whether TRIP13 can complement the defect of the yeast pch2 gene. Using a yeast deletion strain lacking pch2, we integrated plasmids containing either the yeast pch2 or the human TRIP13 gene, both harboring the wild-type or the mutant allele and assessed the crossingover rate between marker genes lys2 and leu2 as a measure of complementation. Evidence is presented that the human plasmids, unexpectedly also that with the mutation, could complement the pch2 deficient yeast strain, underlining that the evolutionary conservation at the molecular level obviously extends to the functional level.

Background: Nanopore sequencing is a technology that holds great promise for identifying all types of human genome variations, particularly structural variations. In this work, we used nanopore sequencing technology to sequence 2 human cell lines at low depth of coverage to call copy number variations (CNV), and compared the results variant by variant with chromosomal microarray (CMA) results.

Results: We analysed sequencing data using CuteSV and Sniffles2 variant callers, compared breakpoints based on hybrid-SNP microarray, nanopore sequencing and Sanger sequencing, and analysed CNV coverage. From a total of 48 high confidence variants (truth set), variant calling detected 79% of the truth set variants, increasing to 86% for interstitial CNV. Simultaneous use of the 2 callers slightly increased variant calling. Both callers performed better when calling CNV losses than gains. Variant sizes from CMA and nanopore sequencing showed an excellent correlation, with breakpoints determined by nanopore sequencing differing by only 20 base pairs on average from Sanger sequencing. Nanopore sequencing also revealed that four variants concealed genomic inversions undetectable by CMA. In the 10 CNV not called in nanopore sequencing, 8 showed coverage evidence of genomic loss or gain, highlighting the need to improve SV calling algorithms performance.

Conclusions: Nanopore sequencing offers advantages over CMA for structural variant detection, including the identification of multiple variant types and their breakpoints with increased precision. However, further improvements in variant calling algorithms are still needed for nanopore sequencing to become a highly robust and standardized approach for a comprehensive analysis of genomic structural variation.

This study evaluates the accuracy of ChatGPT in generating chromosomal representations (formulas) based on ISCN rules in clinical cytogenetics. While ChatGPT generated correct answers for simple cases, it frequently failed in complex cases. These findings highlight the limitations of current AI tools in accurate clinical cytogenetic reporting, reinforcing the vital role of skilled clinical cytogeneticists for accurate interpretation and reporting.

Background: Clonal cytogenetic abnormalities in B-lymphoblastic leukemia (B-ALL) include structural and numerical chromosomal alterations, where numerical are the most common aberrations. Inversion 14 [inv(14)] is an infrequent finding in B-ALL, but its prognostic and therapeutic significance has not been previously explored.

Case presentation: A 13-year-old boy diagnosed as B-ALL on bone marrow aspirate by flow cytometry is presented. Fluorescence in situ hybridization (FISH) for B-ALL panel was reported as normal. Nevertheless, his cytogenetic studies performed on bone marrow showed tetrasomy 8 and a pericentric inversion in chromosome 14.

Conclusion: Inversion 14 is a rare finding in B-ALL, and its clinical relevance is worthy of further evaluation. The growing number of such cases reported emphasizes that there exists a possibility of a separate cytogenetic subset with diagnostic, prognostic or even therapeutic relevance.