Search Results (980)

Background: Prenatal detection of fetal structural anomalies often prompts chromosomal analysis; however, chromosomal microarray analysis (CMA) has limited diagnostic yield for monogenic disorders. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying single-gene etiologies, particularly in cases with complex neurodevelopmental phenotypes. Case Presentation: We report a female infant presenting with prenatally detected ventriculomegaly and inconclusive chromosomal testing. Prenatal investigations, including karyotyping and genome-wide chromosomal sequencing, identified several copy number variants classified as variants of uncertain significance but failed to establish a definitive diagnosis. Postnatally, the patient developed progressive neurological abnormalities, including microcephaly, facial dysmorphism, dystonic movements, and severe global developmental delay. Trio-based whole-exome sequencing identified a heterozygous de novo pathogenic missense variant in the DDX3X gene (c.976C>T; p.Arg326Cys), establishing the diagnosis of DDX3X-related neurodevelopmental disorder. Conclusions: This case highlights the diagnostic limitations of standard prenatal chromosomal testing in detecting monogenic neurodevelopmental disorders and underscores the critical role of timely genetic counseling and exome sequencing. Earlier selective implementation of WES during pregnancy could have enabled an earlier diagnosis, improved prognostic counseling, and optimized clinical decision-making. Full article

Background and Objectives: This study aimed to describe the clinical characteristics and survival outcomes of three representative complex karyotype soft tissue sarcoma (STS) subtypes—undifferentiated sarcoma (US, primarily undifferentiated pleomorphic sarcoma (UPS)), myxofibrosarcoma (MFS), and leiomyosarcoma of soft tissue (LMS-ST)—using data from a single-institution cohort. Materials and Methods: A retrospective review of 124 patients treated at a single tertiary referral center between 2002 and 2024 was conducted. Clinicopathologic characteristics and survival outcomes were analyzed. Kaplan–Meier methods were used to estimate overall survival (OS). Cox proportional hazards regression models were applied to identify independent prognostic factors for survival, incorporating variables such as age, sex, tumor stage, and treatment modality. Results: The cohort comprised 36 cases of US, 64 of MFS, and 24 of LMS-ST. OS and survival after cohort enrollment (S-NCC) were evaluated both by subtype and across the entire cohort to assess potential differences across tumor subgroups. In both univariable and multivariable analyses, US subtypes showed poorer survival than MFS and LMS-ST. FNCLCC grade 3 emerged as a significant adverse prognostic factor for survival across all three subtypes. For FNCLCC grade 3 patients, the presence of benign prostatic hyperplasia (BPH) was significantly associated with an increased risk of death. Conclusions: Among the three subtypes, US demonstrated the most aggressive clinical course, MFS was notable for frequent local recurrence but relatively favorable survival, and LMS-ST showed intermediate outcomes. These findings highlight the clinical heterogeneity of complex karyotype STS and provide a foundation for future studies integrating molecular and multi-omics data to refine risk stratification and therapeutic strategies. Full article

Aleppo oak (Quercus infectoria) is among the most industrially and ecologically significant oak species, valued for its medicinal properties and considerable genetic importance. Cytogenetic analysis provides critical insight into evolutionary history, interspecific relationships, and karyotypic differentiation. This study investigated the chromosomal architecture and karyotypic diversity of five natural populations of this species in western Iran (Sardasht, Oramanat, Baneh, Paveh, and Marivan) using actively dividing root meristems and a high-resolution image-based cytogenetic system. All examined cells displayed a basic chromosome number of x = 12 and a diploid condition, and chromosome lengths ranged from 0.90 to 2.12 µm. ANOVA and mean comparisons of five chromosomal parameters (Long Arm, Short Arm and Total Length, Arm Ratio, and Centromeric Index) revealed significant interpopulation differences in chromosome length and arm dimensions. All populations shared the karyotype formula 12 m and were classified into Stebbins’ Category B, indicating a moderately symmetrical, relatively primitive cytogenetic structure. Principal component analysis reduced the dataset to two major axes explaining 99.93% of the total variance, predominantly influenced by SA and TL on PC1 and by LA, AR, and CI on PC2. Hierarchical clustering grouped the populations into three distinct lineages, with Sardasht–Oramanat–Baneh showing the greatest divergence. Biplot vector patterns further clarified trait correlations, highlighting genomic structuring and potential breeding utility. Full article

Background: Macrocytosis commonly develops during imatinib therapy, but its relationship with cytogenetic and molecular outcomes in chronic myeloid leukemia (CML) remains unclear. We investigated whether increases in mean corpuscular volume (MCV) during imatinib treatment are associated with response depth and treatment persistence. Methods: In this retrospective study, we analyzed 101 adults with chronic-phase CML treated with a stable imatinib dose of 400 mg/day for at least 12 months. Patients with conditions that could confound MCV (hydroxyurea exposure, megaloblastic anemia, hypothyroidism, chronic liver disease, alcoholism) were excluded. Complete cytogenetic response (CCyR) and major molecular response (MMR) were assessed by conventional karyotyping and the BCR-ABL1 International Scale, respectively. Increased MCV was defined as MCV > 100 fL after six months of therapy, persisting thereafter. Associations between MCV dynamics, response, and switching to second-generation tyrosine kinase inhibitors were evaluated. Results: Twenty patients (20%) developed increased MCV. Overall, 86 patients (85%) achieved CCyR and 70 (69%) achieved MMR. All patients with increased MCV attained CCyR, compared with 66 of 81 (81%) without MCV elevation (p = 0.037), while MMR rates were 90% versus 64% (p = 0.030). During a median follow-up of 69 months, treatment modification was required in 1 of 20 (5%) patients with increased MCV versus 25 of 81 (31%) in the non-increased group (p = 0.018). Conclusions: MCV elevation during imatinib therapy is associated with deeper molecular response and reduced need for treatment modification. MCV dynamics may serve as an inexpensive pharmacodynamic marker to support risk assessment and guide monitoring in chronic-phase CML. Full article

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation sequencing (NGS), and immunogenetic assessment of immunoglobulin heavy chain variable region (IGHV) somatic hypermutation status, each of which interrogates only a limited aspect of disease biology. Methods: We retrospectively evaluated fifty patients with CLL using OGM and integrated these findings with cytogenomics, targeted NGS, IGHV mutational status, and clinical time-to-first-treatment (TTFT) data. Structural variants were detected using OGM and pathogenic NGS variants were derived from a clinical heme malignancy panel. Clinical outcomes were extracted from the electronic medical record. Results: OGM identified reportable structural variants in 82% (41/50) of cases. The most frequent abnormality was del(13q), observed in 29/50 (58%) and comprising 73% (29/40) of all OGM-detected deletions with pathologic significance. Among these, 12/29 (42%) represented large RB1-spanning deletions, while 17/29 (58%) were focal deletions restricted to the miR15a/miR16-1 minimal region, mapping to the non-coding host gene DLEU2. Co-occurrence of adverse lesions, including deletion 11q/ATM, BIRC3 loss, trisomy 12, and deletion 17p/TP53, were recurrent and strongly associated with shorter TTFT. OGM also uncovered multiple cryptic rearrangements involving chromosomal loci that are not represented in the canonical CLL FISH probe panel, including IGL::CCND1, IGH::BCL2, IGH::BCL11A, IGH::BCL3, and multi-chromosomal copy-number complexity. IGHV data were available in 37/50 (74%) of patients; IGHV-unmutated status frequently co-segregated with OGM-defined high-risk profiles (del(11q), del(17p), trisomy 12 with secondary hits, and complex genomes whereas mutated IGHV predominated in OGM-negative or structurally simple del(13q) cases and aligned with indolent TTFT. Integration of OGM with NGS further improved genomic risk classification, particularly in cases with discordant or inconclusive routine testing. Conclusions: OGM provides a comprehensive, genome-wide view of structural variation in CLL, resolving deletion architecture, identifying cryptic translocations, and defining complex multi-hit genomic profiles that tracked closely with clinical behavior. Combining OGM and NGS analysis refined risk stratification beyond standard FISH panels and supports more precise, individualized management strategies in CLL. Prospective studies are warranted to evaluate the clinical utility of OGM-guided genomic profiling in contemporary treatment paradigms. Full article

Background: Fetal growth restriction (FGR) is a significant obstetric complication associated with increased perinatal morbidity and long-term developmental risks. Despite advances in prenatal diagnosis, the genetic etiology of isolated FGR remains incompletely characterized, complicating genetic counseling and clinical management. Objective: This study aimed to systematically evaluate the genetic causes of isolated FGR by integrating karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (trio-WES) and to assess the incremental diagnostic yield of this sequential approach. Methods: A retrospective cohort of 153 fetuses with isolated FGR (diagnosed by ultrasound between February 2018 and July 2024) underwent karyotyping and CMA. Cases with normal results from both tests (n = 50) were subsequently analyzed by trio-WES. Results: Karyotyping identified chromosomal abnormalities in three cases (2.0%). CMA detected pathogenic/likely pathogenic copy number variations (CNVs) or uniparental disomy (UPD) in twelve cases (7.8%), including the three karyotypic abnormalities and nine additional cases (5.9% incremental yield). Trio-WES performed on 50 CMA-negative cases identified pathogenic or likely pathogenic variants in 12 cases (24%). Among these, seven cases (14% of the WES subgroup) harbored variants directly causative of FGR, including one case of UPD(6) missed by CMA alone. Additionally, trio-WES revealed seven incidental pathogenic/likely pathogenic variants not directly linked to FGR and identified one case in which FGR was attributed to maternal hyperphenylalaninemia. Conclusions: The sequential application of CMA and trio-WES significantly improves the diagnostic yield for isolated FGR. Trio-WES proved particularly valuable in detecting UPD and single-gene variants missed by CMA alone and in revealing contributory maternal genetic conditions. These findings support the integration of advanced genetic testing into the diagnostic workup for isolated FGR to enhance etiological diagnosis, facilitate comprehensive genetic counseling, and inform multidisciplinary management. Full article

Background: KMT2A partial tandem duplication (PTD) occurs in approximately 5–10% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. While its cytogenetic and molecular features are well described, the immunophenotypic characteristics of AML with KMT2A-PTD remain incompletely defined. Methods: We identified 47 cases of AML with KMT2A-PTD by optical genome mapping. All cases underwent flow cytometric immunophenotypic analysis and next-generation sequencing using an 81-gene panel. Results: The cohort included 32 men and 15 women with a median age of 67 years (range, 19–87). Thirty-eight cases were de novo AML, and nine were secondary to myelodysplastic syndrome and/or myeloproliferative neoplasm. Most cases (93%) demonstrated a normal or non-complex karyotype. The most frequent mutations involved FLT3-ITD (47%), DNMT3A (43%), and RUNX1 (23%). Thirty-one cases (66%) were granulocytic, while 16 (34%) showed granulocytic and/or monocytic differentiation. Blasts uniformly expressed HLA-DR and frequently expressed CD117 (91%) and CD34 (79%). Increased expression of CD123 (74%) and CD117 (43%) and decreased expression of HLA-DR (74%) and CD38 (69%) were common. Aberrant CD25 expression was observed in 51% of cases. Increased CD123 and aberrant CD25 expression were significantly associated with FLT3-ITD mutations (both p < 0.0001) but not with other recurrent mutations. There was no correlation between FLT3-ITD mutation and expression levels of CD117, CD38 or HLA-DR (all p > 0.05). Conclusions: AML with KMT2A-PTD shows distinctive immunophenotypic features with increased CD123 and aberrant CD25 expression, both associated with FLT3-ITD. These markers may have diagnostic and therapeutic relevance in this AML subtype. Full article

Background: The International Consensus Classification (ICC) currently proposes an empirical variant allele frequency (VAF) threshold of 10% to define TP53-mutated acute myeloid leukemia (AML) and to distinguish oncogenic driver from concomitant mutations. However, the optimal cutoff remains uncertain, and the biological and clinical features of low-VAF cases have not been systematically characterized. Methods: In this single-center retrospective cohort study, we stratified TP53-mutated AML by a 10% VAF cutoff and compared clinical characteristics, cytogenetic and molecular profiles, and survival outcomes between groups. Results: The VAF < 10% group exhibited a distinctive profile: fewer adverse cytogenetic abnormalities [complex karyotype, −7, −5/del(5q)], a more adverse molecular profile (EVI1 overexpression, greater co-mutation burden, higher frequencies of ASXL1 and SRSF2 mutations), and a higher proportion of CD34⁺CD38⁻ blast immunophenotype. TP53 hotspot mutations were also more common. Survival analyses showed poor prognosis in both groups, and the VAF < 10% group showed numerically longer survival without statistical significance, indicating no clear survival advantage for low VAF. Conclusions: These data support the clinical relevance of the ICC 10% threshold. TP53-mutated AML with VAF < 10% may represent a biologically distinct subgroup. Further multicenter studies with larger cohorts are needed to validate and refine the VAF threshold for prognostic evaluation and individualized management. Full article

Each year, around 23 million miscarriages occur worldwide, which have a substantial emotional impact on parents, and impose significant societal costs. While medical care accounts for most expenses, work productivity loss contributes significantly. Addressing underlying causes of miscarriage could improve parents’ mental health and potentially their economic impact. In most countries, investigations into miscarriage causes are only recommended after recurrent cases, focusing mainly on maternal factors. Fetal and placental tissue are rarely examined, as current guidelines do not advise routine genetic analyses of pregnancy tissue, because the impact of further clinical decision making and individual prognosis is unclear. However, this leaves over 90% of all miscarriage cases unexplained and highlights the need for alternative methods. We therefore conducted a narrative review on genetic analysis, autopsy, and imaging of products of conception (POC). Karyotyping, QF-PCR, SNP array, and aCGH were reviewed in different research settings, with QF-PCR being the most cost-effective, while obtaining the highest technical success rate. Karyotyping, historically being considered the gold standard for POC examination, was the least promising. Post-mortem imaging techniques including post-mortem ultrasound (PMUS), ultra-high-field magnetic resonance imaging (UHF-MRI), and microfocus computed tomography (micro-CT) show promising diagnostic capabilities in miscarriages, with micro-CT achieving the highest cost-effective performance. In conclusion, current guidelines do not recommend diagnostic testing for most cases, leaving the majority unexplained. Although genetic and imaging techniques show promising diagnostic potential, they should not yet be implemented in routine clinical care and require thorough evaluation within research settings—assessing not only diagnostic and psychosocial outcomes but also economic implications. Full article

Complex genetic syndromes represent a diagnostic challenge due to their diverse phenotypic presentations, which often evolve over time and may not be fully evident at birth. Disorders of sex development (DSD) comprise congenital conditions with discordance between chromosomal, gonadal, and/or genital sex. In 46,XY gonadal dysgenesis, undervirilisation or female-appearing genitalia may occur despite a normal karyotype, and diagnosis increasingly relies on genomic approaches. Prenatal and postnatal growth failure has been described in patients with syndromic 46,XY DSD. We report a male patient with SGA, lack of postnatal catch-up growth, and syndromic dysgenetic 46,XY DSD followed longitudinally from infancy to 11 years, in whom whole-exome sequencing (WES) reanalysis revealed a pathogenic 2.7 Mb microdeletion at 3q27.1q27.2. Systematic review of previously reported 3q27.1 deletions identified overlapping phenotypes but limited documentation of gonadal dysfunction. Curation of 71 genes within the deleted region highlighted DVL3 and CLCN2 as potential contributors to the gonadal phenotype, although functional evidence remains lacking. This case expands the phenotypic spectrum of 3q27.1 microdeletion syndrome, suggesting that 46,XY gonadal dysgenesis may represent an under-recognised feature. It also underscores the importance of copy number variant (CNV) analysis and periodic re-evaluation of sequencing data to increase diagnostic yield. Full article

Tartary buckwheat has increasingly become the focus of people’s attention due to its powerful health benefits. Golden buckwheat is a traditional Chinese medicine. People have begun to utilize it through wide hybridization to further enhance the health benefits of Tartary buckwheat. To study the genetic stability of the interspecific hybrids of Tartary buckwheat with golden buckwheat, and to provide scientific basis for the interspecific cross breeding of buckwheat, the mitotic chromosomes of two buckwheat double lines and their interspecific hybrids with golden buckwheat were subjected to observe the karyotypes. The results showed as follows: (1) The two autotetraploid Tartary buckwheat lines (Long Black-4T and Daku-1) have chromosome number 2n = 32. The karyotype formula of 2n = 4x = 32 consisted of 16 pairs of metacentric chromosomes for Long Black-4T (TTTT) while Daku-1 (TTTT) has 1sm + 7m Gui Jinqiao 4 with 2n = 32 has a karyotype formula of 2n = 4x = 32 that consisted 1sm + 6m + 1M (genome M) and 2sm + 5m + 1M (genome M’). The normal fertile tetraploid hybrid F1 plants between Long Black-4T and Gui Jinqiao 4 has 2n = 4x = [1sm + 7m (M), 1sm + 7m (M’), 14m + 2M (TT)]. The normal fertile variety Gui Jinku 1 from the above hybrid progenies shows 2n = 4x = [3sm + 5m (M), 2sm + 6m (M’), 16m (TT)], indicating an increment of sm chromosomes by rearrangements of chromosome structure in the M and M’ genomes. The above parents and their hybrids with the MM’TT genome show fertility. A plant from F2 of the above cross, showing highly infertility, has 2n = 3x= [1sm + 7m (M), 1sm + 7m (M’), 8m (T)]; and back cross progeny plant from Daku 1/Gui Jinqiao 4 F2//Gui Jinqiao 2 golden buckwheat has 2n = 4x = [16m (MM), 5sm + 3m (M’), 1sm + 7m (T)], showed high infertility, which is caused by genome aneuploidy and non-even ploidy. The above shows that there are obvious variations of genome karyotypes from the same parent, indicated by certain chromosome structural rearrangements in genomes T, M, and M’. Full article

The assembly of telomere-to-telomere (T2T) genomes is essential for understanding genomic architecture, especially in fungal pathogens with complex karyotypes, such as Colletotrichum lini, causing flax anthracnose disease. This study provides optimized guidelines for the T2T genome assembly using Oxford Nanopore Technologies (ONT) R9.4.1 and R10.4.1 sequencing data processed with the Hifiasm 0.25.0 assembler (with --ont module). We analyzed ONT sequencing data for four C. lini strains and compared basecalling tools (Guppy and Dorado), read filtration strategies (quality thresholds Q10/Q15 and length cut-offs 5 kb/10 kb), and genome coverage levels from 5× to 160×. Our results demonstrated that Dorado-basecalled reads consistently had higher average quality, especially the R10.4.1 data, leading to improved telomere resolution and complete mitochondrial genome assembly. Moderate genome coverage (40–65×) combined with Q15 quality and 5 kb length filtration for R10.4.1 data, or Q10 and 5 kb for R9.4.1 data, produced the most contiguous and complete assemblies. Overfiltration of reads by length and quality or conversely excessive coverage (>90×) reduced assembly quality, causing fragmentation or erroneous chromosome merging. With optimized parameters of ONT R9.4.1 and R10.4.1 sequencing data preprocessing, Hifiasm efficiently generated T2T and near-T2T assemblies of C. lini genomes: 53.7–56.1 Mb length, 13–30 contigs, 12–13 chromosomes (including 3–12 T2T chromosomes), complete mitochondrial genome, and >98.5% BUSCO completeness. These findings provide a solid framework for ONT-based fungal genome assembly, facilitating future research on genomic variation and pathogenicity in Colletotrichum and related genera. Full article

Feingold syndrome (FS) is a rare congenital disorder with an autosomal dominant inheritance pattern. Two distinct subtypes are recognized based on their molecular pathology: FS type 1 (FS1) and FS type 2 (FS2). Both types share skeletal anomalies such as microcephaly, brachymesophalangia, and clinodactyly; however, gastrointestinal atresia is unique to FS1. Herein, we report a rare prenatal diagnosis of FS1 in a female fetus. The second-trimester ultrasound revealed bilateral clinodactyly and fetal microcephaly, and the subsequent molecular karyotyping identified a ~342 kb deletion at 2p24.3 encompassing the MYCN gene, confirming the diagnosis. The same deletion was detected in the father, verifying the hereditary pattern. The pregnancy was also complicated by preeclampsia and fetal growth restriction, leading to preterm caesarean delivery at 33 + 3 weeks of gestation. The neonate had microcephaly and clinodactyly but no gastrointestinal defects. In conclusion, high clinical suspicion aroused by identifying ultrasound features of FS can lead to early prenatal diagnosis via molecular karyotyping. Detecting accompanying gastrointestinal disorders that require early operation is crucial for the prognosis, genetic counseling, and prenatal management of the affected families. Full article

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome encompasses a range of Müllerian duct anomalies characterized by congenital absence of the uterus and the upper two-thirds of the vagina in young women who otherwise exhibit normal endocrine function and a 46,XX karyotype. MRKH syndrome can occur in an isolated form (type I) or in association with other congenital anomalies (type II or MURCS association), which may include renal, vertebral, auditory, and cardiac defects. It represents one of the most frequent causes of primary amenorrhea, affecting approximately 1 in every 4000–5000 women. MRKH syndrome often remains undiagnosed until a patient presents with primary amenorrhea, despite normal development of secondary sexual characteristics. Both genetic and non-genetic factors have been proposed as contributing to abnormal embryonic development, although the exact etiopathogenesis remains unclear. Imaging plays a key role in the evaluation of genital tract anomalies, allowing non-invasive and comprehensive assessment. Alongside physical examination and pelvic ultrasound, pelvic MRI is essential for identifying the presence of rudimentary uterine tissue. MRKH syndrome can have profound and lasting psychological impacts, making it essential for patients and their families to receive counseling both before and throughout treatment. A range of therapeutic options—both surgical and non-surgical—have been proposed for managing MRKH syndrome. Vaginal dilation remains the first-line treatment, as it offers high success rates with minimal risk of complications. Vaginoplasty is considered a second-line option for patients who do not respond to dilation therapy. Additionally, uterine transplantation and gestational surrogacy provide opportunities for women with MRKH syndrome to achieve biological motherhood. This review provides an updated overview of Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, encompassing its etiological, clinical, diagnostic, psychological, therapeutic, and reproductive aspects. We also present a case involving a 19-year-old woman with MRKH syndrome who presented with primary amenorrhea, highlighting the crucial role and advantages of MRI in diagnosis, differential assessment, and treatment planning. Full article

Background and Clinical Significance: Kidney transplant recipients have a 2–4-fold higher cancer risk than the general population. The sequential occurrence of multiple myeloma (MM) and native-kidney renal cell carcinoma (RCC) is rare and creates competing priorities between anti-myeloma efficacy and allograft preservation. Case Presentation: A 54-year-old woman with a 2020 living-donor kidney transplant presented in 2024 with bone pain and shoulder swelling. Low-dose whole-body CT showed multiple punched-out osteolytic lesions. Work-up revealed IgG-κ M-protein 38.5 g/L and 25% clonal plasma cells; cytogenetics showed a complex karyotype (R-ISS III). First-line bortezomib/cyclophosphamide/dexamethasone (VCd) was given while maintaining tacrolimus plus low-dose steroid. After four cycles, she achieved very good partial response (M-protein 42.3 to 5.6 g/L) with stable graft function. Follow-up imaging detected a large exophytic mass in the native right kidney; nephrectomy confirmed papillary RCC, type II. Later, the myeloma progressed with epidural extension causing cord compression. Second-line daratumumab/carfilzomib/dexamethasone (DKd) and palliative spine radiotherapy were initiated. The course was complicated by opportunistic infection and pancytopenia, and the patient died in January 2025. Conclusions: Vigilant post-transplant cancer surveillance—including native-kidney RCC—tailored immunosuppression, and multidisciplinary coordination are critical. VCd with tacrolimus may be feasible when graft preservation is prioritized; however, relapsed high-risk MM on DKd carries substantial infectious risk and a guarded prognosis. Full article