Molecular Cytogenetics最新文献

Neutropenia has been recognized as a common feature of Cohen Syndrome, but its role as an early manifestation has not been fully elucidated. In this report, we present three patients diagnosed with Cohen Syndrome who were referred for neutropenia. All patients exhibited consistent clinical features of Cohen Syndrome, with neutropenia being the indication for genetic research. Neutropenia was the most prominent finding in all patients, and in one case, it was the earliest finding with other specific features. Additionally, we identified two novel variants, c.6107del (p.Asp2036Valfs*3) and c.5703del (p.Arg1901SerfsTer10) in the VPS13B gene, further contributing to the genetic understanding of this syndrome. Our findings emphasize the importance of early recognition of neutropenia as a key clinical sign in the diagnosis of Cohen Syndrome. Furthermore, these novel variants expand the genetic spectrum of the disorder and highlight the need for continued genetic investigation in rare syndromes.

Background: Patients with tendinopathy (TD) have expressed dissatisfaction with the efficacy of the first-line treatment, indomethacin. This research aims to identify key biomarkers in TD and investigate their underlying mechanisms.

Methods: Tendon samples were harvested from 5 Sprague-Dawley (SD) rats exhibiting TD and 5 healthy normal controls (NCs), destined for transcriptome sequencing. After thorough preprocessing of the RNA sequencing data, a differential expression analysis was performed to identify genes that significantly differentiated the TD group from the NCs. To identify candidate genes, an intersection analysis was performed between the differentially expressed genes (DEGs) and the key module genes obtained through weighted gene co-expression network analysis. The candidate genes underwent Mendelian randomization (MR) analysis and least absolute shrinkage and selection operator analysis to identify key genes. We conducted experimental validation and sensitivity analyses, such as pleiotropy, heterogeneity, and leave-one-out evaluations, to ensure the robustness of our findings.

Results: The findings present new evidence indicating that SLC8A1 facilitates the progression of TD. MR analysis established a causal link between SLC8A1 and TD progression (p < 0.05). The study indicated that SLC8A1 might inhibit TD progression by negatively regulating gamma-glutamylisoleucine levels. In SD rats, TD led to a disordered arrangement of collagen structures, increased infiltration of inflammatory cells, increased cell density, and thicker inflammatory hyperplasia in tendon. These results confirm the effective creation of a TD model. Analysis showed significant upregulation of SLC8A1 expression in the TD group (p < 0.05).

Conclusion: This research highlights SLC8A1 as a potential biomarker in TD development, providing novel perspectives for clinical diagnosis and treatment strategies.

Background: Chronic Myeloid Leukemia (CML) is primarily driven by the Philadelphia chromosome, producing the BCR::ABL1 fusion protein. Although imatinib significantly improved CML outcomes, resistance remains a key challenge. Resistance often leads to cytogenetic abnormalities (ACAs), indicating poor disease prognosis. This is the first study that investigates genetic profiles in imatinib-resistant Indonesian CML patients.

Method: The study included adult chronic-phase CML patients who met the criteria of treatment failure under the treatment of imatinib. Peripheral blood samples and bone marrow samples were collected and then processed for cytogenetic examination following the International System of Human Cytogenetic Nomenclature (ISCN) guidelines. BCR::ABL1 transcript levels were measured using Quantitative Real-Time PCR.

Result: Out of 27 CML patients, the mean age was 39.15 years, with a male-to-female ratio of 1:1.5. The mean BCR::ABL1 international scale (IS) value was 37.20 ± 4.56, and patients on tyrosine kinase inhibitor (TKI) therapy had a median treatment duration of 80 months. Cytogenetic analysis showed Philadelphia chromosome (Ph) positivity in 11.11% of peripheral blood and 34.78% of bone marrow samples, with Ph negativity in 25.93% and 17.93%, respectively. Peripheral blood abnormalities included trisomy 8 (11.11%), additional Ph (7.41%), trisomy 19 (3.70%), and complex karyotypes (14.81%), while bone marrow abnormalities included trisomy 8 (13.04%), additional Ph (8.69%), trisomy 21 (4.35%), monosomy 7/7q- (8.70%), and complex karyotypes (43.45%).

Conclusion: Cytogenetic anomalies such as trisomy 8, trisomy 19, and complex karyotypes may contribute to TKI resistance. Further study is needed to understand additional abnormalities observed.

Deletions in chromosome 4p can lead to two distinct phenotypes, Wolf-Hirschhorn syndrome (WHS) and proximal 4p deletion syndrome. While WHS, associated with distal deletions, has well-characterized phenotypic features, proximal 4p deletion syndrome, involving the 4p14-p 16.1 region, shows moderate manifestations, and its causative gene remains unknown with fewer reported cases. Here we report a Chinese case: a 21-year-old female with a peripheral blood chromosomal karyotype of 46,XX, del(4)(p15.3-p16). NGS-CNVA further revealed an 11.7 Mb deletion in the 4p16.2-p15.32 region and a 1.25 Mb microduplication in 16p13.13. She had ovarian dysfunction, and moderate Intellectual Disability(ID) without typical proximal 4p deletion phenotypes. Through analysis of Genecards and OMIM databases, we identified two neurodevelopmental genes DRD5 and WFS1, and four ovarian dysfunction-related genes WFS1, CC2D2A, PROM1, and QDPR, suggesting their roles in the patient's manifestations. Additionally, a review of 37 published cases of proximal 4p deletion syndrome revealed 17 cases with an overlap in the deleted region with our case. This report not only enhances the recognition of this rare syndrome among clinicians but also provides a basis for further exploration of the potential causative genes, contributing to a better understanding of the genotype-phenotype correlations in proximal 4p deletion syndrome.

Background: 16p13.11 Microduplication is a rare genetic disorder with variable expression and incomplete penetrance, primarily reported in adults and children, with limited information available on fetal cases. This study aims to analyze the characteristics of prenatal diagnosis indications and postnatal follow-up in fetuses with 16p13.11 microduplication, and to explore the genotype-phenotype correlation for improving genetic counseling and patients' care.

Methods: A total of 4552 pregnant women who underwent amniocentesis for SNP-array were retrospectively analyzed at the prenatal diagnosis department of Chengdu Women's and Children's Central Hospital from March 2022 to February 2024.

Results: SNP-array identified a microduplication at the 16p13.11 region in 14 fetuses, with sizes ranging from 0.8 to 1.65 Mb. Among the indications for prenatal diagnosis, Case 1, 13, 14 (3/14) presented a high-risk screening result for Down syndrome, Case 5, 8, 10,11 (4/14) demonstrated advanced maternal age, Case 7 (1/14) demonstrated abnormal reproductive history, Case 4 (1/14) demonstrated the pregnant woman was a known carrier of the 16p13.11 microduplication, and Case 2, 3, 6, 9, 12 (5/14) demonstrated ultrasound structural abnormalities. Only 5/14 underwent family verification, and all were inherited from one parent. 2/14 chose to terminate pregnancy, while the remaining cases resulted in term delivery. During follow-up, all but three cases showed no significant abnormalities: one had severe sensorineural hearing loss, one exhibited mild developmental delay, and one was diagnosed with a ventricular septal defect.

Conclusions: These findings indicate that fetuses with 16p13.11 microduplication typically exhibit a nonspecific prenatal phenotype but may be highly correlated with ultrasound abnormalities. Most affected individuals were in good health during follow-up. Furthermore, a systematic review of medical history, genetic diagnosis, and follow-up data could be useful for genetic counseling and patients' growth management.

Keywoeds: 16p13.11; microduplication; SNP-array; prenatal diagnosis; follow-up.

Background: Gene fusions define leukemia subtypes, predicting prognosis and guiding treatment. The classical t(8;21)(q22;q22) translocation results in the RUNX1::RUNX1T1 fusion, characteristic of favorable risk acute myeloid leukemia (AML). To date, more than 21 genes have been identified as partners of RUNX1, each associated with a distinct impact on behavior and outcome. Traditional cytogenetic and molecular techniques often fail to detect cryptic or complex rearrangements, resulting in suboptimal risk assessment. This is a relapsed case of t(8;21) AML involving the rare partner gene PLAG1, identified by optical genome mapping. A review of published cases highlights the distinct prognosis of this fusion.  CASE PRESENTATION: A 71-year-old female previously diagnosed with AML, developed a cytogenetic clone with t(8;21)(q?12-13;q22) at relapse. FISH showed RUNX1 rearrangement, without RUNX1T1 involvement. RT-MLPA and Next Generation Sequencing showed KMT2A partial tandem duplication and pathogenic variants in ASXL1, PHF6, RUNX1 and SF3B1. Customized FISH probes identified the breakpoint within the region spanning PLAG1, confirmed as a translocation partner by OGM. The patient showed disease refractoriness despite multiple lines of chemotherapy and died 17 months after diagnosis.

Discussion and conclusions: PLAG1 is a rare translocation partner of RUNX1 in AML, mistaken for classical t(8;21) on conventional karyotyping. The rare reported cases of PLAG1::RUNX1 suggest a distinctly poor prognosis, highlighting the importance of accurate diagnosis and the role of OGM in our practice.

Background: Myeloid/Lymphoid Neoplasms (MLN) with eosinophilia and PDGFRB rearrangements are rare but distinct hematologic malignancies driven by the constitutive activation of the PDGFRB tyrosine kinase through gene fusions. These neoplasms are sensitive to tyrosine kinase inhibitors (TKIs) such as imatinib, which often leads to rapid and durable molecular remissions. However, diagnostic challenges frequently arise from cryptic rearrangements, necessitating comprehensive molecular approaches.

Case presentation: A 37-year-old male patient initially presented with pancytopenia and a splenic infarct; subsequent bone marrow findings were suggestive of a myeloid/lymphoid neoplasm. Initial conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) identified a PDGFRB gene rearrangement but were unable to fully resolve the structural complexity of the underlying genomic alteration. Long-read sequencing helped resolve a complex three-way translocation involving chromosomes 5, 12, and 20, precisely defining the ETV6::PDGFRB fusion with base pair resolution, and identified the partner gene (KAT14) on chromosome 20p. Following the diagnosis, the patient was started on imatinib therapy and has since achieved clinical and hematological improvement.

Conclusion: This case highlights the significant diagnostic utility of long-read sequencing in uncovering and characterizing cryptic and complex genomic rearrangements that are frequently missed by conventional methods. Accurate molecular characterization is critical for disease classification, guiding targeted therapeutic decisions, and ultimately improving patient outcomes in PDGFRB-rearranged neoplasms.

Background: Monosomy 18p (MIM: 146390) is a well-known chromosomal disorder associated with intellectual disability, short stature, and non-specific craniofacial features resulting from partial or total deletion of the short arm of chromosome 18. The differential diagnosis is broad due to nonspecific and variable phenotypes. The majority of 18p monosomy cases result from de novo deletions, while the remainder are either caused by de novo translocation with loss of 18p, malsegregation of a parental translocation or inversion, or the presence of a ring chromosome or isochromosome 18q. Establishing the etiopathogenetic mechanism is essential to properly assess the risk of recurrence. Chromosomal Microarray Analysis (CMA) has enabled better genotype-phenotype correlations. Nonetheless, CMA is not appropriate for characterizing complex or balanced structural variants, which may underlie complex rearrangement, and the resolution of karyotype analysis is limited.

Case presentation: Here, we report the first case of a derivative 18p interstitial monosomy caused by a maternal complex intrachromosomal rearrangement, fully characterized by Optical Genome Mapping (OGM).

Conclusions: This rearrangement could not be fully characterized by either CMA or karyotype analyses, both of which yielded only partial and inconclusive results. The integration of OGM into routine diagnostics could enhance the understanding of complex chromosomal rearrangements, leading to improved prognostic and reproductive risk assessment.

Objective: This study aimed to characterize the prenatal features, inheritance patterns, and outcomes of 1q21.1 copy number variations (CNVs) and refine prenatal counseling strategies.

Methods: We conducted a retrospective analysis of 20 consecutive prenatal cases diagnosed with 1q21.1 CNVs between 2017 and 2024. Genetic testing included karyotyping, chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq). Phenotypic data, inheritance patterns, and pregnancy outcomes were evaluated.

Results: The cohort comprised 12 microdeletions (60%) and 8 microduplications (40%). Ultrasound anomalies were detected in 66.7% (8/12) of microdeletion cases (e.g., fetal growth restriction, cardiac defects) and 37.5% (3/8) of microduplication cases (e.g., nasal bone hypoplasia). No specific prenatal ultrasound markers pathognomonic for 1q21.1 CNVs were identified. Termination of pregnancy (TOP) was elected in 50% (10/20) of cases, predominantly for de novo CNVs (80% of TOP decisions). Among live-born infants (n = 9), no overt abnormalities were detected during postnatal follow-up (3 months to 5 years).

Conclusion: Prenatal 1q21.1 CNVs demonstrate incomplete penetrance and variable expressivity, without consistent association with specific prenatal ultrasound markers. The TOP rate for de novo CNVs reflects profound parental anxiety regarding neurodevelopmental outcomes. These findings underscore the critical need for comprehensive prenatal counseling that integrates genomic findings, phenotypic severity, and psychosocial support.

Background: Sexual differentiation and development rely upon many genetic and environmental factors and any disruption of these can lead to Differences/Disorders of Sex Development (DSDs). DSDs are a diverse group of heterogeneous rare diseases that can be categorized into three main groups. 46,XY, complete gonadal dysgenesis is a subgroup of 46,XY, DSD that appears as female phenotype and external genitalia characterized by primary amenorrhea at adolescent.

Case presentation: Here, we present a 14-year-old female patient with structural rearrangements of the Y chromosome including SRY gene duplication. These chromosomes were characterized by karyotyping, Oligo-array comparative genomic hybridization (CGH), metaphase fluorescence in situ hybridization (FISH), and exome sequencing (ES). The mechanism(s) by which these rearrangements could have occurred is discussed.

Conclusions: 46,X, idic(Y)(p11.32→q11.22:: q11.22→p11.32)] in this proband led to a large copy-number change including 24.5 Mb gain on the Yp11.32q11.223 region and a 33 Mb loss on the Yq11.223q11.23 region.