Introduction: Cytogenetic findings are essential for diagnosis and prognostic risk stratification in hematologic malignancies. However, the extent to which routine karyotype reports incorporate clinically relevant interpretation remains variable. This study evaluated the completeness, accuracy, and clinical integration of cytogenetic reporting. Methods: We retrospectively reviewed 225 consecutive bone marrow karyotype reports issued between October 2020 and July 2024 from a tertiary-care cytogenetics laboratory. Reports were assessed for interpretive commentary, disease-specific risk stratification, actionable testing recommendations, genetic counseling referral, turnaround time (TAT), and ISCN accuracy. Risk stratification analyses were restricted to cases eligible for established disease-specific frameworks (107/225; 47.6%). Results: ISCN errors were identified in 72/225 reports (32.0%), most commonly involving bracketing and subclone notation. Explicit risk-tier documentation was present in only 3/225 reports (1.33%). Among AML cases with documented risk assessment, misclassification occurred in 3/15 cases (20.0%), whereas no misclassification was observed in MDS. Actionable testing recommendations were documented in 5/225 reports (2.22%), and 4/225 reports (1.78%) contained ISCN results without interpretive narrative. Genetic counseling recommendations were absent from all reports, including four cases meeting predefined criteria. Median TAT was 30.5 days (IQR 23–44; 90th percentile 72.3 days), exceeding recommended benchmarks. Conclusions: Cytogenetic reporting gaps primarily reflect limited clinical interpretation rather than technical reporting deficiencies. Standardized diagnosis-aware templates and quality monitoring may improve reporting completeness, consistency, and clinical utility.
Introduction: Complex chromosomal translocations can obscure the identification of pathogenic rearrangements involving KMT2A in acute myeloid leukemia (AML). Case Presentation: We report a 20-year-old female with AML harboring a novel three-way translocation, t(9;11;19)(p21;q23;q13.1), resulting in a KMT2A::MLLT3 fusion. The patient presented with gingival swelling, oral ulcers, anemia, thrombocytopenia, leukocytosis, and 95% peripheral blasts. Flow cytometry showed blasts expressing CD11c, CD13, CD33, CD38, CD64, CD117, and HLA-DR. Conventional cytogenetics and KMT2A break-apart FISH confirmed rearrangement in nearly all cells. Whole-genome sequencing resolved the structural architecture, identifying a BND-type event fusing KMT2A exon 8 to MLLT3 exon 6, along with a non-functional head-to-head involvement of TBCB. RNA sequencing confirmed the pathogenic KMT2A::MLLT3 transcript without evidence of TBCB fusion or overexpression. Additional NRAS and KRAS mutations were detected. The patient achieved complete remission following induction and consolidation chemotherapy but relapsed one year later. She subsequently underwent allogeneic stem cell transplantation, relapsed four months post-transplant, and died two years after diagnosis. Conclusion: This case represents an exceptionally rare instance of KMT2A::MLLT3 generated through a three-way complex translocation and highlights the utility of whole-genome and transcriptome sequencing in clarifying rearrangement topology. The aggressive clinical course raises important questions about the prognostic implications of structural complexity and cooperating RAS mutations in KMT2A-rearranged AML.
Microdeletion syndromes are rare chromosomal abnormalities causing diverse clinical features due to gene dosage imbalances. Deletions in chromosome 17q23.3 have been linked to neurodevelopmental and growth disorders, although the genotype-phenotype correlations remain unclear. An eight-month-old male baby presented with short stature, low-set ears, cardiac anomalies, and multiple congenital malformations. He was born via C-section due to intrauterine growth restriction and exhibited craniofacial dysmorphism, lymphatic vessel dysplasia, micropenis, undescended testes, atrial septal defect, and subclinical hypothyroidism. The phenotype raised clinical suspicion of Noonan Syndrome. However, exome sequencing revealed no pathogenic variants in RASopathy-related genes. Copy number variant (CNV) analysis identified a ∼1.5 Mb deletion on chromosome 17q23.3, affecting 30 genes, including TANC2, which serves as the primary breakpoint gene and plays an essential role in synaptic development. This case highlights the role of CNV analysis in patients suspected of having Noonan Syndrome with negative single-gene testing and suggests an expanded phenotypic spectrum associated with 17q23.3 microdeletion.
Introduction: Angelman syndrome (AS) is an imprinting disorder that arises almost exclusively through maternal mechanisms; most commonly maternal 15q11.2-q13 deletion; less often, paternal uniparental disomy (UPD) of chromosome 15. Paternal transmission of a 15q11.2-q13 deletion typically results in Prader-Willi syndrome, making familial paternal AS transmission exceptionally rare. Herein, we report a pedigree in which a neurotypical father transmitted AS to multiple offspring via a structural mechanism distinct from UPD. Case Presentation: The progenitor exhibited 47,XY,+mar[24]/46,XY [6] mosaicism by G-banding karyotype, with three distinct cell lines identified by fluorescence in situ hybridization analysis: a deleted lineage (SNRPN-; 25%), a balanced lineage (SNRPN+ on sSMC; 45%), and a dosage-rich lineage (SNRPN++ on sSMC; 30%). The sSMC is proposed to have originated through a trisomic rescue event; in which an initial trisomy 15 conceptus underwent rescue with retention of deleted region material on the marker, enabling somatic compensation in the progenitor. Notably, UPD was excluded as the pathogenic mechanism in affected offspring. Instead, the sSMC's mitotic instability likely facilitated transmission of the unbalanced deletion without the compensatory marker, whereas its structural interference with the imprinting center prevented the maternal-to-paternal epigenetic reset, resulting in an AS phenotype. Conclusion: This report highlights the role of sSMCs in masking pathogenic deletions and underscores the diagnostic importance of high-resolution genomic mapping in cases of atypical imprinting transmission.
Cytogenetic variation and chromosomal evolution in Palearctic white-toothed shrews (Crocidura) remain poorly understood, particularly within the Asian clade. Here, we provide the first cytogenetic characterization of Crocidura kegoensis and Crocidura dracula from Vietnam. All studied C. kegoensis individuals have stable karyotypes with 2n = 40 and FNa = 52 and are distinguished by large heterochromatic blocks on sex chromosomes. Different C. dracula specimens with equal FNa = 52 have 2n = 36-38 due to centromeric fusions. To enable comparative analysis within and beyond the genus, we generated a flow-sorted library for Crocidura sibirica and applied fluorescent in situ hybridization (FISH) to C. dracula metaphase chromosomes. Integrating our cytogenetic data with existing genetic evidence, we confirmed the presence of two distinct groups within the Asian clade of Palearctic shrews - northwestern and southeastern - that differ both genetically and karyologically. Using C. dracula as a focal taxon, we highlight ongoing, rapid speciation within the southeastern group and show that the extent level of chromosomal rearrangements in taxa correlates with their divergence time.
