Partial gene duplications are structural variants that are challenging to interpret, particularly in the context of neurodevelopmental disorders. The ASH1L gene, associated with autism spectrum disorders and cognitive impairment, exemplifies the complexity of such variants. This study explores the integration of Optical Genome Mapping (OGM) with traditional cytogenetic techniques and RNA sequencing to enhance the characterization of de novo partial gene duplications.

Copy number variations (CNVs) of uncertain significance (VUS) are increasingly identified through prenatal and postnatal genetic testing, yet their clinical interpretation remains challenging. We report a neonate with hematologic and genitourinary anomalies in whom a de novo duplication at chromosome 2q23.1-2q23.3 was discovered, prompting further genomic and clinical investigation.

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.

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.

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.

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.

Kaufman oculocerebrofacial syndrome (KOS; OMIM #244450)is a rare autosomal recessive disorder caused by pathogenic biallelic variants in UBE3B, characterized by craniofacial dysmorphism, global developmental delay, hypotonia, and multisystem anomalies.

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.

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.

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.

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.

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.

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.

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

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.

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).

Peutz–Jeghers syndrome is an autosomal dominant disease characterized by intestinal polyposis, mucocutaneous pigmentation, and an increased risk of various types of cancer. Germline mutations in (), which encodes serine/threonine kinase 11, have been identified as the major cause of Peutz–Jeghers syndrome. Here, we detected a rare variant of undetermined significance in intron 2 of using multi-gene panel analysis in a girl with clinically suspected Peutz–Jeghers syndrome. We confirmed this variant caused abnormal splicing in exons 2 and 3 using reverse transcription-PCR and Sanger sequencing. To validate the predicted impact of this variant on splicing, we performed functional analysis using a minigene assay. Functional analysis experiments demonstrated that this variant suppresses normal splicing, and the clinical significance of the STK11 variant, which was initially considered a variant of “uncertain significance,” was reclassified as “likely pathogenic” based on functional analysis. The interpretation of U12-type intronic variants remains particularly challenging due to limited data and the absence of specific recommendations in existing guidelines [1, 2], and when segregation analysis is difficult, functional analysis from splicing assays is essential to provide accurate genetic diagnosis and information for clinical management. However, further familial segregation analysis and further validation of potential exon-skipping events are necessary to fully characterize the splicing impact of this variant.

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.

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.

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.

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.