Background: The BCR::ABL1 gene fusion is the hallmark of chronic myeloid leukemia (CML). Variant Philadelphia chromosome (Ph)-positive cases with complex chromosomal rearrangements involving additional chromosomes occur in 4-11% of c ases, but their prognostic significance remains unclear. Methods: A 20-year-old male presenting with leukocytosis and anemia was evaluated using conventional cytogenetics, fluorescence in situ hybridization (FISH), and reverse transcription PCR (RT-PCR) to identify chromosomal abnormalities and BCR::ABL1 transcript type. Results: Cytogenetic analysis revealed a novel balanced five-way translocation: 46,XY,t(9;10;15;21;22) (q34;p11.2;q22;q22;q11.2). FISH confirmed the BCR::ABL1 fusion in 97% of nuclei, and RT-PCR detected the e13a2 (p210) BCR::ABL1 transcript. The patient exhibited rapid progression to blast crisis and resistance to first-line imatinib therapy. Conclusion: This novel five-way translocation in Ph-positive CML highlights the importance of comprehensive cytogenetic and molecular characterization to detect rare variants that may influence treatment response and prognosis.
Traditionally limited to rare diseases, genomics is shifting toward broad clinical application.
Background: Noonan syndrome (NS) is an autosomal dominant condition characterized by facial dysmorphism, congenital heart disease, growth impairment, and ectodermal findings. Variants in SOS1 account for a large proportion of cases. Case presentation: We report a male infant with nasal bone hypoplasia and shortening of long bones identified during the prenatal period. After birth, he presented with facial dysmorphism, pulmonary valve stenosis, axial hypotonia, and renal anomalies. The karyotype was normal. Whole-exome sequencing with CNV analysis focused on NS-related genes identified a heterozygous SOS1 variant, c.1656G>T (p.Arg552Ser), classified as pathogenic according to ACMG criteria and curated databases, supporting the diagnosis of SOS1-related Noonan syndrome type 4. The SOS1 p.Arg552Ser variant has been reported in individuals with typical NS features, supporting the genotype–phenotype correlation. In this patient, the combination of prenatal skeletal markers and postnatal renal involvement illustrates the wide phenotypic variability. Early molecular confirmation allowed multidisciplinary care and targeted surveillance (cardiac, endocrine, and oncologic), as well as genetic counseling. Conclusion: This case highlights the diagnostic utility of early exome sequencing when NS is suspected, but the phenotype is incomplete, and emphasizes the value of integrating prenatal markers with postnatal findings to enable timely management guided by precision medicine.
Objective: This study aimed to study knowledge, attitude, and practice regarding the health risks of consanguineous marriage (CM) among the population in the Western region of Saudi Arabia. Methods: A cross-sectional study was conducted among a total of 1,789 adults aged 18 years and above, residing in the Western region of Saudi Arabia, from June to July 2025, using a snowball sampling technique. An online questionnaire was designed based on a literature review. Results: The participants were predominantly females (70.3%), aged 21-30 years (42.3%), and university educated (58.0%), with 20.4% working in medical professions. Of the 762 who responded to the consanguinity question, 33.2% reported being in a CM, mostly with the first cousin (25.2%). Overall mean knowledge score was 73.4% ± 26.4%, with 80.8% scoring above 50%; mean attitude score was 70.1% ± 9.1, with 98.4% scoring above 50%. Knowledge gaps were identified in awareness of premarital screening components (26.4% correct) and availability of premarital whole exome sequencing (51.6% correct). Female gender, younger age (18-20 years), university or high school education, and healthcare employment were independently associated with higher knowledge scores (p < 0.05). Attitudes were uniformly positive toward genetic screening but varied toward CM. In practice, 60% reported avoiding CM if screening results were incompatible. Conclusion: While general knowledge and attitudes toward genetic screening were favorable, substantial educational gaps persisted, particularly regarding available testing and residual genetic risk. This highlighted the need for targeted public health education and campaigns for older, less-educated, and non-healthcare populations.
Background: Sickle cell disease (SCD) is a hereditary blood disorder with high prevalence among tribal populations in India. This study uniquely evaluates the impact of genetic counselling on disease awareness and mental health in India’s tribal communities, where limited access to such services exacerbates disease burden. Methods: A qualitative, cross-sectional study involved 35 participants aged 20–44 years in a high-risk tribal region of Maharashtra, India. Participants included one SCD patient, one caregiver, one community health worker (CHW), two healthcare professionals (a hematologist and a psychiatrist), and 30 community members. Semi-structured interviews, developed through literature review and pilot-tested, explored SCD knowledge, preventive strategies, and psychological well-being. Thematic analysis compared outcomes between counselled (n=18) and non-counselled (n=17) participants. Results: Counselled participants demonstrated greater knowledge of SCD’s genetic basis (94% vs. 24%), symptoms (89% vs. 35%), and preventive measures (83% vs. 12%), such as premarital screening. They also showed higher engagement in community initiatives (83% vs. 12%) and reported reduced anxiety (78% vs. 29%), improved coping, and greater emotional resilience. Non-counselled participants often misidentified SCD as an infection (59%) or general anemia (41%) and reported higher stress (71%) and sleep disturbances (53%). Conclusion: Genetic counselling significantly enhances SCD awareness and psychological resilience in tribal communities. Expanding culturally tailored counselling services is critical to reducing SCD burden in underserved areas.
Inborn errors of metabolism (IEMs) caused by a deficit of some specific metabolic pathways are phenotypically heterogeneous complex disorders. Although in recent years metabolomics has helped in understanding the pathophysiology of IEMs, its challenges and limitations such as false positives and negatives result in delayed diagnosis and postponed treatment. This leaves the physician with a large list of differential diagnosis among IEMs. Early and accurate diagnosis in case of suspicious IEMs can be lifesaving, especially for conditions those are treatable. Recently, next-generation sequencing (NGS)-based whole-exome sequencing proved to be an efficient technology in enhancing the accuracy of diagnosis of metabolic disorders, especially for complex disorders. It offers a broader range of disorders diagnosed at an affordable cost compared to metabolomics. The aim of this article is to provide insights into bridging metabolomics and NGS-based genomics to improve diagnostic yield in complex IEMs, while also emphasizing the role of genetic counselling in empowering families and improving patient quality life.
Background: Transaldolase deficiency (TALDO-D, Eyaid syndrome) is a rare autosomal recessive disorder of the pentose phosphate pathway. It can present prenatally with intrauterine growth restriction or oligohydramnios; neonatally with dysmorphic features, cardiovascular defects, hepatosplenomegaly, anemia, and thrombocytopenia; or later with a milder phenotype. The present case report aimed at enhancing the effectiveness and confidence in treating patients with rare metabolic disorders that are further complicated by complex presentation. Case Presentation: We present a rare case of a 14-year-old girl diagnosed with Eyaid Syndrome - TALDO-D based on clinical and molecular findings of a homozygous pathogenic variant in the TALDO1 gene, c.793del, p.(Gln265Argfs*56). She developed type 1 diabetes around the age of nine and was found to have a baseline non-anion gap metabolic acidosis that persisted despite adequate diabetes management. An extensive workup for possible renal causes, given that they are part of her primary syndrome, revealed proximal renal tubular acidosis. During an emergency department visit, she presented with abdominal pain, vomiting, diarrhea, and lethargy. Laboratories showed severe metabolic acidosis (pH of 6.93, HCO3– of 3.3), marking the beginning of her challenging management approach. Conclusion: The patient in this case report has shown an excellent response to sodium bicarbonate in a well-monitored clinical and biochemical setting. However, given the rarity and complexity of such cases, it is imperative to conduct a comprehensive literature review involving all relevant subspecialties and report similar challenging cases to establish evidence-based clinical practices for the high-quality management of this rare patient population.
Background: The autoinflammatory pancytopenia syndrome (AIPCS) is a rare autosomal recessive disease caused by a mutation in the DNASE2 gene that is characterized by severe anemia, thrombocytopenia, hepatosplenomegaly, and recurrent fevers. Case Presentation: A case of a preterm female neonate born at 30 + 1 weeks by emergency cesarean section of consanguineous parents was presented, with subsequent antenatal findings of intrauterine growth restriction, fetal anemia, and hypertrophic cardiomyopathy. Postnatal evolution was conducted during admission to neonatal intensive care, with features of apnea, respiratory distress syndrome, persistent pancytopenia, and progressive hepatosplenomegaly. Laboratory and radiology findings indicated that a metabolic and genetic cause was likely, with suspicion raised of an interferon-mediated inflammation disorder. A genetic evaluation by whole exome sequencing showed a compound heterozygous DNASE2 variant of uncertain significance (141_142del (p.Gly48AlafsTer49) and c.2T>C (p.Met1)). Ruxolitinib, a JAK inhibitor, was initially offered and later deferred due to prematurity and low birthweight, which started at the age of 5 months. Conclusion: A rare genetic disease causing early-onset systemic autoinflammatory disease due to DNASE2 mutation was identified. This study emphasized the importance of early detection and the establishment of genetic diagnostic methods for severe, multisystem, idiopathic neonatal inflammatory syndromes to prevent the progression of disease.
Background: Developmental and epileptic encephalopathies (DEEs) are severe disorders marked by refractory seizures and developmental delay. Pathogenic variants in the syntaxin-binding protein 1 (STXBP1) gene are among the top five genetic causes of DEE and impair neurotransmitter release, especially in GABAergic interneurons. The clinical presentation is highly variable, and diagnosis depends on molecular genetic testing. Precision medicine is key for diagnosis, treatment, follow-up, prognosis, and hereditary risk reduction. Case Presentation: We present a male patient with drug-resistant epilepsy, polypharmacy, and cognitive impairment, without significant family or perinatal risk factors. Given the clinical complexity and strong suspicion of genetic cause, a molecular study using next-generation sequencing of epilepsy-related genes and copy number variation analysis was performed. A heterozygous pathogenic variant in STXBP1, c.1652G>A (p.Arg551His), was identified, associated with early infantile epileptic encephalopathy type type 4, also known as STXBP1-DEE (MONDO:0012812 - orphanet identifier (ORPHA):599373], with autosomal dominant inheritance. Conclusion: STXBP1-DEE represents a heterogeneous spectrum of neurodevelopmental disorders with refractory epilepsy, developmental delay, and intellectual disability. Diagnosis requires clinical suspicion, imaging, laboratory tests, and molecular confirmation. While current treatments are limited, promising approaches are under investigation. The lack of genotype-phenotype correlation and wide phenotypic variability complicate management, but advances in precision medicine support more individualized treatment strategies. Although most variants are de novo, genetic counseling remains crucial to assess recurrence risk. Preclinical studies show potential for novel therapies, yet clinical trials are needed to confirm their efficacy in affected individuals.
Background: The cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is linked to gastrointestinal inflammation and has been implicated in early-onset malignancies. However, its role in gastric cancer remains poorly understood. Aims: To investigate the CFTR interactome and assess its potential functional involvement across different subtypes of gastric cancer. Methods: We conducted a system-level in silico analysis using data from the Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). CFTR expression and co-expression profiles were examined across molecular and histological subtypes of gastric cancer, including signet-ring cell carcinoma (Lauren’s classification). Differential gene expression (DGE) and co-expression analyses were integrated with protein-protein interaction networks, pathway enrichment, and gene ontology (GO) analysis to delineate CFTR’s functional associations. Results: CFTR did not exhibit significant differential expression across gastric cancer subtypes. However, co-expression analysis identified CFTR as a key hub gene with a distinct interaction network, especially prominent in the signet-ring cell carcinoma subtype. Enrichment analyses revealed that CFTR's interactome is involved in regulatory pathways related to cellular homeostasis, ion transport, and immune modulation, suggesting a noncanonical yet critical role in tumor biology. Conclusion: While CFTR expression remains stable across gastric cancer subtypes, its interactome reveals significant regulatory roles, particularly in signet-ring cell carcinoma. These findings highlight the potential contribution of CFTR to gastric cancer pathogenesis through its involvement in broader molecular networks rather than through expression changes alone.
Background: Opitz G/BBB syndrome (XLOS) is a rare X-linked recessive disorder caused by mutations in MID1 gene, characterized by midline congenital anomalies. Here we report a novel MID1 duplication associated with unique phenotypic features. Case Presentation: A 2-year-old Saudi male had prenatally oligohydramnios and was born with rectovesical fistula, hypospadias, anorectal malformation, and congenital heart defects (ASD/PDA). Family history revealed an X-linked inheritance pattern (multiple affected maternal male relatives). He also exhibited developmental delay and growth parameters below the 3rd percentile Conclusion: This is the first report of a MID1 duplication involving exons 1–3, associated with rectovesical fistula and oligohydramnios, broadening the phenotypic spectrum of XLOS. We recommend that MID1 testing be considered in males with atypical midline defects (including urogenital anomalies) and prenatal testing should be offered for at-risk pregnancies.
Background: Spastic ataxia type 5 (SPAX5) is a rare autosomal recessive neurodegenerative disorder that is characterized by a progressive combination of spasticity, cerebellar ataxia, and difficulties with fine motor coordination. This report aims to highlight the clinical profile, diagnostic findings, and genetic aspects of SPAX5, emphasizing the value of Whole-exome sequencing in diagnosing rare hereditary disorders. Case Presentation: In this report, we present the clinical progression, findings, and genetic classification of a 47-year-old male diagnosed with spastic ataxia type 5, who, over the past decade, has experienced worsening balance instability, weakness, and increasing walking disturbances. Upon follow-up, he presented with gaze palsy and a noticeable decline in cognitive function. Family history noted a cousin aged 60 with similar symptoms, consistent with the autosomal recessive inheritance pattern characteristic of SCA5. Genetic analysis: Whole exome sequencing (WES) revealed a homozygous likely pathogenic variant in the AFG3L2 gene, confirming the diagnosis of SPAX5. This discovery emphasizes the genetic etiology of the disease and underscores the role of familial inheritance in its pathogenesis and progression. Conclusion: This case stresses the value of genetic testing, particularly WES, in diagnosing disorders like SPAX5, which often present with nonspecific clinical manifestations and overlap with other neurodegenerative disorders. It also further illustrates the importance of community-based genetic studies to better understand the inheritance patterns of rare hereditary disorders and to enhance management strategies.
Genetic disorders remain among the greatest challenges in modern medicine, with over 95% lacking curative therapies. Preimplantation Genetic Testing (PGT) has emerged as a transformative preventive tool, enabling the detection of chromosomal abnormalities (PGT-A) and single-gene disorders (PGT-M) in embryos prior to implantation. At ExpressMed Diagnostics and Research, Bahrain, nearly 700 PGT-A and 25 PGT-M cases have been performed, with a significant impact on reducing miscarriage risk and preventing sickle cell disease transmission. Our data highlight the critical influence of maternal age, with aneuploidy rates rising from ~60% in women under 30 to ~90% in women over 40. In the Gulf region, where consanguinity and genetic disorders are highly prevalent, PGT offers a powerful public health strategy to reduce inherited disease burden, complementing newborn screening and premarital testing. As genomic technologies advance, ensuring accessibility, affordability, and ethical oversight will be essential. PGT represents not only a scientific breakthrough but also a shift in reproductive medicine from treatment to prevention, with profound implications for future generations.
Background: Hepatocellular carcinoma (LIHC) is a common and aggressive liver malignancy, often diagnosed at advanced stages. Dysregulation of the TP53 tumor suppressor gene critical for cell cycle control, apoptosis, and genomic stabilityis frequently observed in LIHC; however, its prognostic value remains uncertain. Objectives: To investigate TP53 expression levels, prognostic relevance, and molecular interactions in LIHC within a broader pan-cancer context. Methods: Publicly available datasets from TCGA and GEO were analyzed. TP53 differential expression was evaluated using TIMER 2.0, GEPIA, and UALCAN. Survival analysis was performed via Kaplan-Meier Plotter, GEPIA, and UALCAN. Genomic alterations were assessed through cBioPortal. Gene expression validation was conducted using GEO2R and ggplot2. Protein-protein interaction networks were constructed using STRING and GeneMANIA. Results: TP53 mRNA expression was significantly elevated in LIHC tumor tissues compared to normal liver tissues (p < 0.05). Promoter hypo-methylation was noted in tumor samples, potentially contributing to this up-regulation. Survival analysis revealed conflicting findings: Kaplan-Meier Plotter associated high TP53 expression with better prognosis (HR = 0.65, p = 0.029), whereas GEPIA and UALCAN linked high expression with poorer outcomes. Furthermore, TP53 expression positively correlated with immune cell infiltration and advanced clinical stage, suggesting a complex role in tumor progression. Conclusion: TP53 demonstrates a dual, context-dependent role in LIHC, acting as both a tumor suppressor and potential oncogenic driver. Its variable expression patterns and inconsistent prognostic associations highlight its potential as a diagnostic and prognostic biomarker and support the need for further functional and clinical validation.
Background: Polydactyly is common congenital limb anomaly characterized by having extra fingers or toes and can be either syndromic or non-syndromic. GLI3 plays an important role in limb development via the Sonic Hedgehog signaling system. Methods and Results: In this study, we examined a Pakistan family with postaxial polydactyly in an autosomal dominant manner. Clinical assessment confirmed non-syndromic presentation without further systemic abnormalities. Whole exome sequencing and Sanger validation identified a novel heterozygous missense variant in GLI3 (Glioma-associated oncogene homolog 3) [NM_000168.6: c.3199C>T; p. (Pro1067Ser)]. Conclusion: This novel variant expands the GLI3 mutation spectrum and highlights the importance of comprehensive genetic screening for accurate diagnosis and counselling of families with isolated polydactyly.
Premarital genetic screening (PGS) refers to the procedure whereby couples are tested for genetic abnormalities before marriage in order to determine the likelihood that their future children may inherit certain genetic conditions. This screening can lower the prevalence of genetic illnesses and assist potential parents in making educated reproductive decisions.
Background: Lipoprotein lipase deficiency (LPLD) is an exceedingly rare autosomal recessive disorder characterized by severe hypertriglyceridemia and significant clinical complications, notably recurrent acute pancreatitis. Case Presentation: We present the detailed case of a Saudi girl who initially exhibited severe hypertriglyceridemia at 3 months old and received a genetic diagnosis at 8 months, confirming homozygous LPL deficiency (variant c.765_766del). Despite rigorous dietary management and medium-chain triglyceride supplementation, she experienced multiple episodes of necrotizing pancreatitis. Conclusion: This report underscores the essential role of early genetic confirmation, rigorous dietary management, multidisciplinary care, and explores emerging treatment strategies for LPLD.
The SWItch/Sucrose Non-Fermentable chromatin remodeling complex, particularly the SMARCA5 gene and its product circSMARCA5, holds significant implications for understanding nucleosomal transformations, gene regulation, and cancer development. Additionally, the concept of cancer stem cells (CSCs) and their role in malignancies sheds light on the complex nature of cancer progression and the potential for targeted therapeutic interventions. The circSMARCA5 expression showed a significant and opposite association with its parent gene in breast cancer, indicating its potential as a therapeutic target for breast cancer treatment. CSCs in breast cancer share similarities with normal stem cells and exhibit disrupted signaling pathways, emphasizing the importance of identifying CSCs for understanding disease biology and developing targeted therapies. Additionally, research revealed circSMARCA5 expression is reduced in nonsmall cell lung cancer (NSCLC), and its overexpression impedes the proliferation, migration, and invasion of NSCLC, indicating its potential as a prognostic indicator for lung cancer patients. The CSCs have been identified in small cell lung cancer, contributing to tumor development, treatment resistance, and potential metastasis through the process of epithelial- mesenchymal transition, and are characterized by the overexpression of specific signaling pathways and cell surface markers. The current understanding of circSMARCA5's role in breast and lung malignancy highlights its significant contribution to tumor development and potential clinical applications, paving the way for promising therapeutic interventions in cancer treatment. This opens new avenues for personalized medicine and novel strategies for cancer management in the future.
Objectives: Our objective was to identify the genetic cause in a patient with intellectual disability and bilateral cataracts. Methods: The genetic, neurological, and ophthalmological evaluations were performed. DNA samples were provided from the patient, parents, and unaffected sibs to perform whole exome sequencing (WES) and Sanger confirmation. Biochemical testing on the serum sample was performed to ascertain the clinical significance of the WES finding. Results: The proband presented with intellectual disability, subtle dysmorphic features, and bilateral cataracts. WES and segregation studies using Sanger sequencing revealed a homozygous missense variant of uncertain significance (VUS) in SRD5A3 and a de novo pathogenic frameshift variant in PITX3 in the proband. Biochemical analysis of serum carbohydrate-deficient-transferrin (CDT) to ascertain the significance of the VUS in SRD5A3 was consistent with a glycosylation defect and confirmed type 1, N-glycosylation defect. Conclusion: This case has a dual molecular diagnosis. The SRD5A3 variant with confirmed biochemical abnormality accounts for intellectual disability and subtle dysmorphic features, whereas the de novo pathogenic PITX3 variant accounts for bilateral cataracts. This case expands the severity spectrum of SRD5A3 disorder and represents a milder form. It also highlights the importance of clinical correlation and reverse phenotyping.
Background: Sensorineural hearing loss is among the most common sensory defects worldwide. Nonsyndromic hearing loss (NSHL) accounts for 70% of inherited hearing loss. The genetic causes of NSHL are considered heterogeneous. The high rate of consanguineous marriages in Saudi Arabia increases the population's prevalence of autosomal recessive inheritance patterns. Objective: To discover a novel variant for NSHL patients. Methods: A family with two hearing-impaired children was recruited. Targeted exome sequencing, the Twist Exome 2.0 kit (Twist Bioscience) using the Novaseq X plus platform, was used to identify the variant. Sanger sequencing was carried out to confirm the finding and perform segregation analysis. MutationTaster tool was used to determine the pathogenicity effect on the protein structure. Results: A homozygous two-bp duplication variant on the (c.8813_8814dup) MYO15A gene was identified in a Saudi family of two hearing-impaired children. Sanger sequencing confirmed the variant in the affected children and their parents. The prediction tool indicated the frameshift effect on the protein level, which leads to protein function disruption. Based on the American College of Medical Genetics and Genomics guidelines, it is classified as a pathogenic variant. Conclusion: A novel biallelic frameshift variant in MYO15A causes NSHL in a Saudi family. This variant is considered rare and isolated to the Saudi population. Expanded genotype-phenotype correlations for hearing loss patients are likely to confirm the findings and reveal novel variants.
