PurposeDespite the rapid expansion of noninvasive genomic technologies, invasive procedures such as chorionic villus sampling (CVS) remain indispensable for providing definitive, early prenatal genetic diagnoses. This study aimed to assess the diagnostic value and effectiveness of CVS in the early detection of chromosomal and genetic abnormalities in a cohort of 912 Polish women.Patients and MethodsThis retrospective cohort study included 912 CVS procedures performed between 2010 and 2024 at a tertiary referral center. Indications, sampling success rates, and genetic results were analyzed. Fetal samples were examined using conventional karyotyping, chromosomal microarray analysis, and digital PCR.ResultsOf 912 procedures, 903 (99.0%) were technically successful, with 844 included in the final cytogenetic analysis. The most common indication was abnormal ultrasound findings (79.9%). Chromosomal abnormalities were found in 40.05% of cases, with trisomy 21 (16.8%), trisomy 18 (8.8%), trisomy 13 (3.1%) and monosomy X (4.6%) being the most frequent. Mosaicism was detected in 8 cases, and maternal cell contamination in 9.ConclusionCVS is a valuable method of early prenatal genetic diagnosis, especially in high-risk pregnancies, where early and personalized genomic assessment can have a significant impact on clinical decision-making. Emerging genomic technologies are likely to complement CVS, underscoring its continued relevance in genomic medicine and personalized prenatal care.

Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a clinically and genetically heterogeneous neurodegenerative disorder. ARSACS typically manifests as slowly progressive ataxia with spasticity and sensorimotor neuropathy. Nevertheless, an array of additional features may also be observed, including hearing impairment, epileptic seizures, and even the absence of spasticity. Reports of SACS mutations in Polish patients are rare. Here we report a compound heterozygous pathogenic variants in the SACS gene, a novel duplication of exon 6, and a frameshift deletion c.12923_12927del 12921_12925del p.(Lys4308SerfsTer21) in a Polish patient presenting with progressive ataxia, spasticity, and peripheral neuropathy. This is the first case with a rearrangement of a complete single exon of the SACS gene. We also review six previously described Polish individuals with SACS variants, noting that all presented with cerebellar ataxic gait and cerebellar atrophy on brain MRI scans. Across these cases, nine rare pathogenic SACS variants were identified. This study adds to the ARSACS-associated mutation spectrum, provides further insights into genotype-phenotype correlations, and highlights the importance of testing for structural variants.

ObjectiveTo analyze the incidence of different types of Y chromosome microdeletions in infertile male patients in China, and to investigate the relationship between microdeletions in different azoospermia factor (AZF) regions and sperm kinetic parameters, sperm morphological parameters, and sex hormone levels.MethodsA total of 2010 infertile male patients who visited the Fujian Provincial Maternity and Child Health Hospital from 2022 to 2025 were selected. Their Y chromosome microdeletions (YCMD), semen routine, sperm morphology, sperm DNA fragmentation index (DFI), and sex hormone levels were detected, and the relationships between these parameters were analyzed.ResultsThe incidence of Y chromosome microdeletions in patients was 8.66% (174/2010). Among the 174 patients with AZF microdeletions, the proportion of AZFc region deletions was 85.63% (149/174), AZFa region deletions accounted for 2.30% (4/174), AZFb/c region deletions accounted for 8.05% (14/174), AZFa/b/c region deletions accounted for 2.87% (5/174), and heterochromosome deletions accounted for 1.15% (2/174). There were no statistically significant differences in semen volume, testosterone (T), and prolactin (PRL) levels between patients with different types of AZF deletions and the normal group (P>0.05). There were statistically significant differences in sperm concentration, progressive motility (PR), non-progressive motility (NP), total sperm motility, normal sperm morphology rate, sperm DFI, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) between patients with different types of AZF deletions and the normal group (P<0.05).ConclusionAZFc deletion is the most common type of Y chromosome microdeletion in infertile male patients in China. Patients with AZFa and AZFa/b/c combined deletions often present with azoospermia. AZFc deletion is associated with abnormal sperm quality parameters and disordered hormone levels.

BackgroundPartial monosomy of chromosome 21q is a rare genetic disorder characterized by a wide spectrum of clinical manifestations including intellectual disability, developmental delay, and distinctive craniofacial features. Concurrent deletions involving chromosome 15q26 are also infrequent and typically benign.ObjectiveThis study reports a rare case of de novo unbalanced translocation between chromosomes 15q26.3 and 21q22.11, resulting in partial monosomy 21q and a benign deletion of 15q26.3, highlighting the importance of comprehensive cytogenetic and molecular analysis.MethodsPeripheral blood samples from the proband and her parents were analyzed using GTG-banding karyotype, fluorescence in situ hybridization (FISH), and whole-genome oligo-array comparative genomic hybridization (array CGH).ResultsThe proband, a 36-year-old woman with intellectual disability and developmental delay, exhibited a karyotype of 45,XX,der(15)t(15;21)(q26.3;q22.11),-21. Array CGH revealed a 17.32 Mb deletion at 21q11.2q22.11 encompassing 37 genes, and a benign 673 kb deletion at 15q26.3 involving 13 genes. Clinical features included multiple craniofacial dysmorphisms, low birth weight, short stature, and dental anomalies.ConclusionThis case represents the first reported instance from Iran of a pathogenic partial monosomy 21q due to an unbalanced translocation with chromosome 15q26.3. The findings underscore the critical role of integrated cytogenetic and molecular diagnostics in identifying complex chromosomal rearrangements and contribute to the understanding of genotype–phenotype correlations in partial monosomy 21q.

BackgroundCharacteristic genetic events underpin acute myeloid leukemia (AML) heterogeneity and enable precise risk stratification. However, prognostic assessment remains ambiguous in many patients due to inadequate integration of specific genetic information.Materials and MethodsEighty NPM1-mutated AML patients were enrolled. Copy number alterations (CNAs) were detected via shallow whole-genome sequencing (sWGS), and concurrent mutations via targeted deep sequencing of myeloid malignancy-associated genes. Clinical and laboratory parameters were integrated with genomic data for statistical analysis, with the aim of assessing the potential clinical significance of CNA profiles in prognostic stratification.ResultsNPM1 mutation subtypes A, B, and D were the most prevalent, with all patients harboring at least two concurrent mutations (4–5 mutations being the most frequent), and these mutations commonly co-occurred with those in FLT3, DNMT3A, TET2, IDH2, and NRAS. Forty-one samples (51%) exhibited CNAs across diverse genomic regions, with dup(18)(p11.23) identified as the most recurrent locus. No significant differences in FAB classification, hematologic parameters, demographic characteristics (gender, age), co-mutation profiles, complete remission (CR) rates, or survival outcomes were observed between the CNA-positive and CNA-negative groups. Univariate survival analysis revealed patients with ≥2 CNAs, or FLT3-internal tandem duplication (FLT3-ITD) had significantly shorter overall survival (OS). Notably, integrative analysis of CNAs with mutational profiles showed that patients harboring both FLT3-ITD and ≥2 CNAs had the poorest OS, followed by those with FLT3-ITD and <2 CNAs, and multivariate Cox regression analysis suggests a potential association between ≥3 CNAs and adverse outcomes; however, given the limited sample size of cases with high CNA burden, this result should be interpreted with caution.ConclusionThis exploratory study suggests that combining CNAs and gene mutation profiles may potentially improve the existing prognostic evaluation system for NPM1-mutated AML patients. Confirmation of these results requires additional validation in larger prospective cohorts.

IntroductionPathogenic variants in the DMD gene maintaining the open reading frame typically cause Becker muscular dystrophy. Here, we report a 7.7-year-old boy exhibiting a severe Duchenne muscular dystrophy phenotype, despite an in-frame deletion of DMD exons 50–51 identified by initial genetic testing, representing a notable exception to the conventional reading-frame rule.MethodsTo elucidate his phenotype-genotype discordance, muscle biopsy and subsequent dystrophin protein and mRNA analyses were conducted, followed by long-read sequencing of DMD gene and splicing analysis.ResultsMuscle biopsy revealed a dystrophic pattern and negative expression of dystrophin-N and dystrophin-C. The dystrophin mRNA analysis identified two out-of-frame DMD transcripts, which were different from the in-frame deletion of DMD exons 50–51 and can explain his severe phenotype. Long-read sequencing uncovered a novel deletion variant (~97kb) in DMD gene, which produced the two out-of-frame transcripts through aberrant splicing.ConclusionThis case underscores the necessity of a stepwise molecular analysis strategy for the interpretation of phenotype-genotype discordance in dystrophinopathy. This stepwise diagnostic approach is essential for accurately characterizing DMD variants, guiding patient management, and genetic counseling.

Thalassemia is a group of inherited blood disorders caused by defects in hemoglobin production, the protein that transports oxygen in red blood cells. These diseases are characterized by either diminished or missing production of one of the globin chains, which are often the alpha or beta chains that comprise hemoglobin. Diagnosis is based on a combination of laboratory tests, including hemoglobin electrophoresis, globin chain chromatography, and genetic analysis. However, diagnosis can become challenging when typical hematological features of thalassemia are not matched by expected biochemical findings. One such situation occurs when HbA2 levels appear normal despite a suspected β-thalassemia trait. This can happen when a β-globin gene variant is present alongside a δ-globin gene pathogenic variant, producing an atypical profile that may mask the true diagnosis. In this case report, we describe a patient carrying a heterozygous β-globin pathogenic variant (HBB c.118C>T; p.Gln40Ter, also known as codon 39) coexisting with a large novel 1.6 kb deletion in the delta-globin gene (HBD) that removes the first two exons. We discuss the diagnostic challenges and clinical implications associated with this rare genetic combination, emphasizing the critical role of comprehensive molecular testing in accurately identifying complex thalassemia cases. This report contributes to the literature by documenting a novel δ-globin deletion in combination with a β-thalassemia variant, providing valuable insights for clinicians and geneticists in the interpretation and management of atypical thalassemia profiles.

BackgroundNon-invasive prenatal testing (NIPT) has emerged as a significant advancement in prenatal screening that offers safer and more accurate detection of chromosomal abnormalities compared to conventional methods. The study aimed to evaluate the status of NIPT adoption in the Kingdom of Saudi Arabia (KSA).MethodsA comprehensive 3-phased study was conducted to examine the status of NIPT in KSA. In Phase I targeted literature review was conducted followed by Phase II and Phase III which involved qualitative interview-based exploration with key stakeholders and round table discussion with key opinion leaders, respectively.ResultsKey stakeholders in KSA underscore NIPT’s clinical value and economic benefits while addressing coverage disparities and the push for national guidelines. In KSA, NIPT prescription is influenced by multiple factors such as logistics, personnel, cost, accessibility, policy, and validation. Addressing these factors is important for the widespread adoption of NIPT as a primary screening test. Key opinion leaders suggest that accurate infrastructure, multidisciplinary care, patient education, and expansion of NIPT’s scope are crucial. To address current challenges, proactive collaboration of both public and private sectors is essential. NIPT usage has increased in KSA over time. It has now been recommended for all pregnant women, leading to an increase in demand for national guidelines to regulate the practice along with awareness campaigns about the value of testing.ConclusionA structured, phased roadmap for implementing NIPT in Saudi Arabia is crucial to ensure cost-effectiveness, cultural and ethical appropriateness, and nationwide access for all pregnant women.

The TTN gene (MIM:188840) encodes titin, the largest human protein with exclusive expression in the cardiac and skeletal muscles. Rare variants disrupting the TTN gene are frequent causes of dilated cardiomyopathy and several forms of skeletal myopathy. We report a unique occurrence of two novel, distinct but overlapping intragenic TTN deletions in multiple relatives from a single Czech family with the clinical manifestation of dilated cardiomyopathy (DCM). After clinical exome sequencing using the custom virtual gene panel, two distinct deletions affecting the TTN gene (NM_001267550.2) were detected. The first deletion (3.599 kb in length) encompasses five exons with the breakpoints in exons 326 and 330. The longer one (4.859 kb in length) disrupts exon 326 only. Both deletions segregate with the cardiomyopathy phenotype, and none of the tested individuals carry both. The familial segregation of two distinct intragenic TTN deletions extends the broad spectrum of rare variants in the pathogenesis of DCM. The presence of severely affected carriers of the reported DNA variants and obligatory healthy non-carriers raises the debate on their ancestral origin. Our data demonstrate the clinical benefits of the family cascade screening and molecular genetic analysis in familial DCM, enabling early and effective multidisciplinary medical care.

IntroductionA lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities.MethodsWhole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0.ResultsThis article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the CUL7 gene.DiscussionThis is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient’s clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.