Search Results (1,031)

Background: Rare diseases collectively affect millions of children worldwide and are a major cause of pediatric morbidity, mortality, and lifelong disability. Although most have a genetic basis, obtaining a timely molecular diagnosis remains challenging because of substantial clinical and genetic heterogeneity. Advances in genomic medicine are transforming rare disease diagnosis and establishing genomics as the center of precision medicine. Methods: This review summarizes current evidence on genomic approaches for pediatric rare diseases, including established and emerging sequencing technologies, their clinical applications, implementation challenges, and future directions. Results: Whole-genome sequencing is increasingly being adopted as a first-line genomic test for suspected rare genetic disorders, particularly when the phenotype is heterogeneous or does not point to a specific diagnosis. Conventional cytogenetic and targeted molecular techniques remain important complementary approaches for selected phenotypes, variant classes, and orthogonal confirmation. Gene panels are effective for well-defined phenotypes, whereas whole-exome sequencing remains a high-yield approach for genetically heterogeneous disorders, particularly when whole-genome sequencing is not available or is not clinically indicated. Long-read whole-genome sequencing expands diagnostic capacity by detecting structural variants, repeat expansions, complex rearrangements, and non-coding pathogenic variants that frequently escape short-read technologies. Emerging multi-omics approaches further improve variant interpretation and help resolve previously unsolved cases. Beyond diagnosis, molecular findings guide personalized clinical management, genetic counselling, reproductive planning, and access to targeted therapies and genotype-driven clinical trials. However, broad implementation is constrained by challenges in variant interpretation, ethical and legal considerations, data governance, workforce capacity, cost, and inequitable access to genomic services. Artificial intelligence, international data-sharing initiatives, and coordinated healthcare networks are helping overcome these barriers and improve diagnostic equity. Conclusions: Whole-genome sequencing is increasingly emerging as a first-line genomic strategy for pediatric rare diseases, while complementary technologies, expert phenotyping, and iterative data interpretation remain essential for comprehensive and accurate diagnosis and equitable access to genomic medicine. Full article

Background/Objectives: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). Results: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. Conclusions: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling. Full article

Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the clinical and molecular characteristics of seven primary classifications: Duchenne muscular dystrophy (DMD), a severe childhood myopathy caused by a complete absence of the protein that leads to loss of ambulation and fatal cardiorespiratory failure in youth; Becker muscular dystrophy (BMD), a milder variant with partial protein deficiency that preserves walking capabilities into adulthood and prolongs life expectancy; pseudometabolic dystrophinopathic syndrome, featuring exercise intolerance, cramps, and recurrent rhabdomyolysis that mimics metabolic diseases; asymptomatic dystrophinopathy, representing the mild end of the spectrum identified incidentally through chronically elevated creatine kinase levels; brain dystrophin-related syndrome, where the disruption of distal isoforms like Dp140 and Dp71 results in neurodevelopmental and neuropsychiatric comorbidities such as ADHD, autism, and intellectual disability; X-linked dilated cardiomyopathy (XLDCM), a cardiac-selective condition causing severe heart failure and arrhythmias while sparing skeletal muscle function; and female dystrophin-related syndrome, distinguishing between familial carriers—who can manifest symptoms due to skewed X-chromosome inactivation—and rare sporadic females who develop an exceptional, severe, Duchenne-like phenotype due to cytogenetic accidents such as Turner syndrome or chromosomal translocations. Ultimately, advancements in molecular testing (NGS and WGS) have significantly optimized diagnostic precision, proving essential for implementing early cardioprotective care, accurate genetic counseling, and the development of future tissue-specific targeted gene therapies. The present study also discusses the psychosocial impact that the disease has on patients. Full article

Background: Variants in SOX4 cause intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF), an autosomal dominant disorder characterized by global developmental delay, mild-to-severe intellectual disability, speech delay, distinctive facial features, digital anomalies, congenital heart defects (unique), and behavioral abnormalities. To date, only a limited number of patients have been described and the phenotypic spectrum of this disorder has yet to be fully delineated. Methods: Clinical data from three patients were collected, including clinical features, growth and developmental profiles, neuropsychological assessments, and urogenital evaluations. Whole-exome sequencing (WES) was performed to screen for candidate variants, and variant pathogenicity was interpreted following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: All three patients carried previously unreported de novo truncating variants in SOX4: c.583C>T (p.Gln195*), c.1347del (p.Cys450Alafs*5), and c.153G>A (p.Trp51*). Regarding the clinical phenotypes, Patient 3 (P3) was similar to previously reported cases, whereas Patient 1 (P1) and Patient 2 (P2) each exhibited distinctive features on the basis of overlapping with previous reports: P1 presented with severe hypospadias accompanied by cryptorchidism; to our knowledge, no case with this predominant clinical feature has been reported previously. P2 exhibited nystagmus, a novel phenotype not yet reported in the literature. Conclusions: We report three previously unreported de novo truncating variants in SOX4, expand the phenotypic spectrum of SOX4-related disorders to include nystagmus for the first time, and document one patient presenting with severe hypospadias and cryptorchidism. Our findings further expand the mutational and clinical phenotypic spectra of SOX4, underscore the marked clinical heterogeneity of this disorder, and provide new evidence to facilitate clinical recognition and genetic counseling. Full article

Background/Objectives: Compound heterozygosity, multilocus molecular diagnoses, mosaicism, uniparental disomy (UPD), and mitochondrial DNA (mtDNA) heteroplasmy are established configuration-dependent diagnostic categories whose interpretation requires consideration of allelic phase, dosage, parental origin, and tissue distribution. This study evaluated their diagnostic contribution and clinical characteristics in pediatric neurodevelopmental disorders (NDDs). Methods: This single-center retrospective cohort study conducted a descriptive cross-phenotypic evaluation of 2162 children in China who underwent clinical genetic testing between 2015 and 2024. The primary analysis focused on confirmed diagnostic configurations, whereas study-defined possibly diagnostic configurations were included only in expanded-set sensitivity and supplementary descriptive analyses. Binary clinical outcomes were adjusted for sex, calendar year of testing, and primary testing strategy. Ascertainment depended on the genetic tests performed for each child rather than systematic screening for all five categories. Results: Confirmed diagnostic configurations were identified in 166/1009 (16.5%) children with definitive molecular diagnoses, corresponding to 166/2162 (7.7%) of the full cohort. These comprised 103 compound heterozygous configurations, 24 multilocus molecular diagnoses, 19 mosaic findings, 4 UPD-related configurations, and 16 mtDNA heteroplasmy configurations. An additional 34 children had possibly diagnostic configurations, yielding an expanded configuration set of 200/2162 (9.3%), which was not interpreted as a definitive diagnostic yield. In the confirmed-only analysis, age at onset was lower than in the comparison group (median 1.80 vs. 2.80 years, Bonferroni-adjusted p = 0.008), and epilepsy was less frequent [94/166 (56.6%) vs. 1338/1962 (68.2%), Bonferroni-adjusted p = 0.035]. Conclusions: Confirmed diagnostic configurations involving these five categories accounted for 16.5% of definitive molecular diagnoses and were characterized by a lower frequency of epilepsy at the cohort level. Configuration-level assessment of allelic phase, dosage, multilocus contribution, parental origin, mosaic fraction, and tissue context may improve diagnostic completeness and recurrence-risk counseling. Full article

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) affects an estimated 6% of adults in the United States and contributes to a significant economic burden. Telehealth has emerged as a vital tool in the management of ADHD, offering improved access to care, especially for individuals in underserved communities. Despite its growing role, there remain critical gaps in understanding how social determinants of health (SDOH) are associated with disparities in telehealth utilization for ADHD treatment. Objectives and Methods: This study analyzed data from the National Center for Health Statistics (NCHS) Rapid Surveys System (RSS) Round 2: ADHD (October–November 2023), a nationally fielded survey of U.S. adults. Respondents were classified into three groups: never diagnosed, previously diagnosed, and currently diagnosed with ADHD. The study aimed to (1) compare the distribution of SDOH across ADHD status groups and the general adult population to identify factors associated with ADHD diagnosis; (2) assess the homogeneity of SDOH distributions across ADHD groups; (3) evaluate telehealth utilization among adults currently diagnosed with ADHD; and (4) examine the relationship between SDOH and telehealth use for ADHD treatment. Multivariable logistic regression (MVLR) served as a benchmark model, while machine learning (ML) models—including regularized linear regression, support vector machine (SVM), random forest (RF), LightGBM, multilayer perceptron (MLP), and Few-Shot Learning (FSL)—were trained to identify key predictors. Results: A total of 7009 survey responses were analyzed: 124 had a past diagnosis, 444 were currently diagnosed, and the remainder had never been diagnosed with ADHD, corresponding to a current ADHD prevalence of 6.3%. Adults with current ADHD were more likely to be male, single, younger, white, non-homeowners, and frequent users of online health resources. They also reported lower education, income, and financial security. About 70% used telehealth for counseling and prescriptions; insurance covered telehealth visits for 82.32% of users, yet 38.76% reported no coverage of ADHD-related diagnostic or treatment costs. Nineteen SDOH elements across four domains—demographic, socioeconomic, neighborhood/built environment, and healthcare access—were identified as predictors. ML models outperformed MVLR, with SVM and FSL achieving the highest F1 (both 0.63), and FSL the highest recall (0.69). Age, race, marital status, difficulty paying bills, home ownership, education, and household size were the most consistently important variables. Limitations: This study is limited by a cross-sectional design, reliance on self-reported ADHD diagnoses, and a lack of genetic or family-history measures. Additionally, the omission of complex sampling weights limits the national representativeness of these findings. Finally, the small effective sample size poses risks of model overfitting, and the generalizability of the models could not be externally validated due to the unavailability of comparable independent datasets. Conclusions: Despite widespread internet access, disparities in telehealth use for ADHD persist. Among 19 SDOH predictors, age (aOR = 0.56), difficulty paying medical bills (aOR = 2.52), and race (aOR = 1.37) were significantly associated with telehealth use, and all ML models outperformed the MVLR benchmark, though bootstrap CIs overlapped. Future research should incorporate inclusive data collection and stratified modeling to better represent disadvantaged populations and inform equitable access strategies. Full article

Background/Objectives: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene. Early diagnosis and appropriate treatment are essential for preventing irreversible complications. This study demonstrated the clinical utility of integrated high-throughput genomic analysis for molecular diagnosis and genetic counseling in a large Thai family affected by WD. Methods: A 32-year-old woman with clinical features suggestive of WD underwent clinical, biochemical, and molecular genetic evaluations, including sequencing of the entire ATP7B gene and SNP microarray. Fluorescent PCR followed by capillary electrophoresis was used for segregation analysis in available family members. SNP microarray analysis and whole-exome sequencing were performed on the proband’s husband to identify pathogenic variants in the ATP7B gene and other disease-associated genes for reproductive risk assessment. Results: The proband presented with hepatic dysfunction, Kayser–Fleischer rings, low serum ceruloplasmin, and a family history of fatal liver disease. She also developed progressive weakness, with nerve conduction findings consistent with axonal sensorimotor polyneuropathy predominantly affecting the lower limbs. Sequencing identified a novel homozygous 28-bp splice-junction deletion, c.4022-24_4025del, which disrupted the canonical splice acceptor site at the intron 19/exon 20 boundary and was classified as pathogenic variant. Segregation analysis confirmed carrier status in the proband’s father and identified heterozygous carrier or homozygous wild-type status among her living siblings. SNP microarray analysis revealed a 46.7 Mb copy-neutral long contiguous stretch of homozygosity (CN-LCSH) encompassing ATP7B, with CN-LCSH regions accounting for 2.046% of the total autosomal genome. These findings potentially reflected segmental uniparental isodisomy or identity by descent, while the overall homozygosity pattern did not support recent consanguinity. Combined genomic analyses of the proband’s husband revealed no pathogenic or likely pathogenic ATP7B variants. Based on the available testing, all offspring are expected to be heterozygous carriers, and the risk of an affected child is considered very low. Conclusions: This study highlights the value of integrated genomic analysis for molecular diagnosis, cascade testing, and reproductive risk counseling. Further functional studies should be conducted to validate their pathogenicity. Full article

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts) syndrome is a rare neurodegenerative inherited disorder characterized by a spectrum of these clinical phenotypes. Due to the considerable heterogeneity in the age of onset of the different clinical features and the similarities with other conditions, it is often misdiagnosed. Variants in the ABHD12 gene have been identified as a genetic cause of PHARC syndrome and are predicted to result in loss-of-function or severely reduced protein synthesis. ABHD12 (α/β-hydrolase domain-containing protein 12) is responsible for the breakdown of very-long-chain lysophosphatidylserines (VLC-lyso-PS). When ABHD12 is dysfunctional, VLC-lyso-PS accumulates in the brain, producing inflammation. In this study, the clinical phenotypes of five patients with molecularly confirmed ABHD12 pathogenic variants from Moorfields Eye Hospital together with those of 64 patients reported in the literature were analyzed to investigate genotype–phenotype correlations. We report a novel variant c.985del p.(His329Thrfs*57) associated with PHARC syndrome. Moreover, patients with two null variants in ABHD12 manifest more of the clinical features of PHARC syndrome than those with at least one missense variant. Our study shows the importance of a complete clinical and genetic diagnosis to enable accurate diagnosis and genetic counselling for affected individuals. Full article

Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early detection can confer health benefits, its identification was not the original objective of the screening. We therefore examined whether genetic forms of MMA can be distinguished from acquired forms. Early distinction between these forms is essential for guiding clinical management, informing prognosis, and enabling appropriate genetic counseling. Specifically, we tested whether the use of Collaborative Laboratory Integrated Reports (CLIR) to complement NBS results improved specificity of the test for genetic MMAs. We found that with the use of CLIR, genetic conditions including methylmalonyl-CoA mutase (mut) deficiency and cobalamin (cbl) A, B, C and D deficiency can be partially differentiated from acquired causes. This results in a significant reduction in the number of second-tier tests required. However, this approach may also exclude certain other genetic causes. Based on all findings, we provide considerations and implications for MMA screening that may inform decision-makers in (other) NBS programs. Full article

Background: Given the rising global prevalence of dementia and its complex etiology, involving genetic and environmental risk factors, the aim of the present exploratory study was to investigate how offspring of individuals with dementia perceive genetic risk and the role of diet in dementia prevention. Methods: A mixed-methods study was conducted in Greece. Overall, 118 offspring completed an online questionnaire assessing demographics, risk perceptions, and dietary beliefs and practices in dementia risk reduction. Additionally, 22 semi-structured interviews explored dietary beliefs, practices, and influencing factors using framework analysis. Results: Most participants (76.3%) recognized diet’s role in dementia prevention, while 52.5% perceived offspring as having increased genetic risk; 40.7% reported making dietary changes to reduce disease risk. Healthcare professional consultation was the factor most strongly associated with dietary modification (OR = 26.61, 95% CI 7.47–94.76, p < 0.001). Qualitative findings showed that, while dementia was viewed as severe, personal susceptibility was often perceived as uncertain or distant. Key barriers, facilitators, and the role of self-efficacy in adopting healthier dietary practices were also explored. Conclusions: Our findings identify personalized dietary counselling and risk communication as priorities for evaluation in future intervention studies, aimed at supporting the implementation of dietary modifications and reducing the gap between knowledge and behavior in dementia risk reduction. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article

Background/Objectives: Recurrent pregnancy loss (RPL) has traditionally been investigated predominantly through maternal factors, while the clinical role of paternal assessment remains inconsistently defined. Current guidelines differ substantially regarding semen analysis, sperm DNA fragmentation (SDF), genetic testing, and referral for andrological evaluation. This review aimed to compare contemporary guideline recommendations, critically appraise the directness, prognostic value, and clinical utility of the supporting evidence, and classify paternal assessment strategies as routine, selective, or investigational. Methods: A structured narrative review was conducted using PubMed and Scopus searches through June 2026. International RPL, obstetric, reproductive medicine, and andrology guidelines were compared. Evidence from systematic reviews, meta-analyses, clinical studies, and clinically relevant molecular investigations was evaluated according to its directness to RPL populations, diagnostic and prognostic value, and evidence that test-guided interventions improve miscarriage or live-birth outcomes. Results: Routine paternal assessment should include age, reproductive and medical history, body weight, lifestyle, medication exposure, and relevant environmental or occupational risks. Conventional semen analysis is appropriate primarily when RPL coexists with infertility or suspected male reproductive disease. SDF is the most extensively studied advanced paternal biomarker and is frequently elevated in RPL cohorts, but findings vary by assay and comparator population, while prospective prediction of subsequent live birth and benefit from SDF-directed treatment remain unproven. Parental karyotyping has established counselling value but should be risk-stratified. Sperm aneuploidy testing, oxidative stress assays, seminal microbiome profiling, epigenetic biomarkers, and biomarker-directed interventions remain investigational. Conclusions: Paternal assessment in RPL should be couple-based, clinically targeted, and evidence-informed. Current evidence supports routine clinical evaluation, selective use of semen analysis, SDF testing, genetic assessment, and reproductive urology referral, and restriction of unvalidated biomarkers and treatments to research settings. Full article

Background/Objectives: Termination of pregnancy (TOP) following a prenatal diagnosis of congenital heart disease (CHD) is a complex decision shaped by clinical, ethical, and psychosocial factors. This study evaluated the clinical factors associated with parental acceptance of TOP after prenatal diagnosis of CHD in a multidisciplinary counselling setting. Methods: This retrospective cohort study was conducted at a tertiary referral center where fetal CHD cases are evaluated in a multidisciplinary perinatology council. Pregnancies with a prenatal CHD diagnosis for which TOP was medically recommended between December 2023 and February 2026 were included. Maternal, fetal, and genetic data were analyzed. Cardiac severity was classified using the fetal cardiovascular disease severity scale. Because the cohort included only 62 pregnancies, a simplified multivariable logistic regression model with three clinically prespecified variables (four parameters: gestational age, cardiac severity, and genetic-evaluation status) was used to identify variables associated with termination acceptance. Results: Sixty-two pregnancies were included; 41 (66.1%) accepted termination and 21 (33.9%) continued the pregnancy. Maternal characteristics and gestational age at diagnosis were similar between groups. In the multivariable model, genetic-evaluation status was the only variable independently associated with termination acceptance. Compared with cases without genetic testing, both major chromosomal/pathogenic anomalies (aOR 4.97; 95% CI 1.29–19.11; p = 0.020) and a normal genetic-evaluation status (aOR 4.71; 95% CI 1.07–20.77; p = 0.041) were associated with higher termination acceptance. Cardiac severity and gestational age were not independently associated with parental decision. Conclusions: Genetic-evaluation status was associated with parental acceptance of termination after prenatal CHD diagnosis in a multidisciplinary counselling setting; given the small sample size and the selected, council-recommended cohort studied, this association should be interpreted as hypothesis-generating rather than as evidence of a causal or independent predictive effect. Full article

Background: Genetic diseases pose a significant public health issue in Saudi Arabia, driven by relatively high prevalence and factors such as consanguineous marriage. Increasing public awareness and understanding are crucial to improving prevention, early detection, and the use of genetic healthcare services. This study aimed to evaluate residents’ knowledge, attitudes, and awareness of genetic diseases in the Qassim region. Methods: A web-based cross-sectional survey was conducted from March to May 2024 among Qassim residents, using an online questionnaire shared via multiple social media platforms. The survey assessed knowledge of genetic diseases, awareness of preventive measures and screening programs, and familiarity with genetic healthcare services. Descriptive statistics summarised the results, and binary logistic regression was conducted to identify factors independently associated with good awareness of genetic testing. Results: Of the 398 participants, about 66% knew about common genetic diseases in Saudi Arabia, while 92% recognised consanguineous marriage as a key cause of genetic disorders. Most respondents correctly identified that genetic diseases are not transmitted through infection (93%). Support for expanding premarital, prenatal, and newborn screening programs was high at 93%, 88.9%, and 90.7%, respectively. Nonetheless, only 38.7% were aware of specialised genetic laboratories and counselling services, and just 4.4% had consulted a genetic counsellor. Social media was the primary source of genetic information (36%). Despite limited awareness of available services, 94% supported establishing a regional genetic testing lab, and 71% were willing to participate in future genetic research. Multivariate analysis identified that marital status is the only variable significantly associated with genetics testing awareness status [aOR = 2.34; 95% CI (1.08–5.08); p = 0.030]. Conclusions: Participants demonstrated generally good knowledge of genetic diseases and positive attitudes towards preventive genetic screening programmes. However, awareness of and utilisation of specialised genetic healthcare services, including genetic counselling and genetic testing laboratories, remained limited. These findings underscore the need to enhance public education, expand genetic counselling, and improve access to specialised services to advance genomic medicine in Saudi Arabia. However, the predominance of younger participants and students may limit the generalisability of the findings to the broader Qassim population. Full article

Background/Objectives: Fetal hepatosplenomegaly is an uncommon but clinically significant prenatal finding associated with a wide range of heterogeneous conditions, including congenital infections, fetal anemia, genetic syndromes, metabolic disorders, and other, less common abnormalities. Because of its nonspecific presentation and diverse etiologies, it represents a diagnostic challenge that requires a structured, multidisciplinary approach. This review aims to present a practical, clinically oriented, stepwise approach to the prenatal evaluation of fetal hepatosplenomegaly, integrating current evidence to facilitate differential diagnosis and guide prenatal management. Methods: A comprehensive literature review was performed, focusing on ultrasound diagnosis, differential diagnosis, genetic evaluation, and prenatal management strategies in fetuses with hepatosplenomegaly. Results: The prenatal detection of hepatosplenomegaly should prompt a detailed ultrasound assessment, including the confirmation of organ enlargement, evaluation of associated structural abnormalities, Doppler studies, and screening for signs of fetal anemia, infection, hydrops fetalis, or cardiac dysfunction. The diagnostic workup should begin with targeted maternal and fetal investigations directed toward the most common causes. In unresolved cases, genetic testing—including chromosomal microarray analysis and next-generation sequencing—may help establish the diagnosis. The preservation of biological material obtained during invasive procedures should be considered to allow future molecular analyses if new clinical findings emerge. The management depends on the underlying etiology and may include fetal therapy, maternal treatment, or specific interventions in selected genetic and metabolic conditions. Conclusions: Fetal hepatosplenomegaly requires a systematic diagnostic strategy that integrates ultrasound, laboratory, and genetic assessment. A structured approach may improve diagnostic accuracy, optimize prenatal counseling, and facilitate the timely management of potentially treatable conditions. Full article