Search Results (409)

Fragile X syndrome (FXS) is the most common form of X-linked intellectual disability (ID). This study aimed to share 30 years of experience in diagnosing FXS and determine its frequency in Thailand. We retrospectively reviewed 1480 unrelated patients (1390 males and 90 females) with ID, developmental delay, or autism spectrum disorder, or individuals referred for FXS DNA testing at Songklanagarind Hospital, Thailand, over a 30-year period. The samples were analyzed using cytogenetic methods, PCR-based techniques, and/or Southern blot analysis. Full mutations (>200 CGG repeats) were identified in 100 males (7.2%) and three females (3.3%). An intermediate allele was detected in one male, while no premutation was found in the index cases. Two males were suspected to have FMR1 gene deletions. Twelve families underwent prenatal testing during this study. Most families undergoing prenatal FXS diagnosis involved mothers who were premutation carriers and had given birth to children affected by FXS. This study represents the largest series of molecular genetic FXS testing cases reported in Thailand. The frequency of FXS identified in different cohorts of Thai patients across various periods was approximately 7%. This study enhances public awareness of at-risk populations and highlights the importance of prenatal testing and genetic counseling for vulnerable families. Full article

Hypoplastic or absent fetal nasal bone (NB) is a significant soft marker in the risk assessment for aneuploidies. This study aimed to evaluate prenatal findings and perinatal outcomes in fetuses with absent or hypoplastic NB managed at our center. This retrospective analysis was conducted at the Department of Obstetrics at the Medical University of Vienna and including all cases with an absent or hypoplastic fetal NB between 2004 and 2022. Clinical data were extracted and analyzed using descriptive statistics. A total of 149 cases were included. Of these, 51% had chromosomal abnormalities, with trisomy 21 present in 30.9%. Malformations were identified in 55% of cases, most commonly congenital heart defects (34.9%) and facial dysmorphism (28.9%). Eighteen fetuses (12.1%) had structural anomalies without genetic disorders. In 32.9% (n = 49), the NB anomaly was isolated. Our findings show that only half of the cases had chromosomal abnormalities, and over half of the pregnancies resulted in live births with generally favorable perinatal outcomes. However, the presence of additional ultrasound abnormalities significantly increased the risk of adverse outcomes. Therefore, detection of a fetal NB anomaly should prompt comprehensive ultrasound evaluation and genetic testing. Full article

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype–phenotype correlation studies. Full article

Massively parallel or next-generation sequencing (NGS) has enabled the genetic characterization of cancer patients, allowing the identification of somatic and germline variants associated with their diagnosis, tumor classification, and therapy response. Despite its benefits, NGS testing is not yet available in the Chilean public health system, rendering it both costly and time-consuming for patients and clinicians. Using a retrospective cohort of 67 formalin-fixed, paraffin-embedded (FFPE) colorectal cancer (CRC) samples, we aimed to implement the identification, annotation, and prioritization of relevant actionable tumor somatic variants in our laboratory, as part of the public health system. We compared two different library preparation methodologies (amplicon-based and capture-based) and different bioinformatics pipelines for sequencing analysis to assess advantages and disadvantages of each one. We obtained 80.5% concordance between actionable variants detected in our analysis and those obtained in the Cancer Genomics Laboratory from the Universidad de Chile (62 out of 77 variants), a validated laboratory for this methodology. Notably, 98.4% (61 out of 62) of variants detected previously by the validated laboratory were also identified in our analysis. Then, comparing the hybridization capture-based library preparation methodology with the amplicon-based strategy, we found ~94% concordance between identified actionable variants across the 15 shared genes, analyzed by the TumorSec^TM bioinformatics pipeline, developed by the Cancer Genomics Laboratory. Our results demonstrate that it is entirely viable to implement an NGS-based analysis of actionable variant identification and prioritization in cancer samples in our laboratory, being part of the Chilean public health system and paving the way to improve the access to such analyses. Considering the economic realities of most Latin American countries, using a small NGS panel, such as TumorSec^TM, focused on relevant variants of the Chilean and Latin American population is a cost-effective approach to extensive global NGS panels. Furthermore, the incorporation of automated bioinformatics analysis in this streamlined assay holds the potential of facilitating the implementation of precision medicine in this geographic region, which aims to greatly support personalized treatment of cancer patients in Chile. Full article

Background: Down syndrome (DS) is a genetic disorder characterized by an extra copy of chromosome 21, often leading to intellectual disabilities, developmental delays, and an increased risk of various comorbidities, including thyroid dysfunction and mental health disorders. The relationship between thyroid dysfunction and mood disorders, particularly depression in DS populations, requires further investigation. Objective: This study aims to investigate the presence of a correlative relationship between hypothyroidism and depression in 178,840 individuals with DS, utilizing data from the National Inpatient Sample (NIS) to determine if those with comorbid hypothyroidism exhibit higher rates of depression compared to their counterparts without hypothyroidism. Methods: A retrospective analysis of the 2016–2019 NIS dataset was conducted, focusing on patients with DS, hypothyroidism, and depression diagnoses. The diagnoses were determined and labeled based on ICD-10 codes associated with NIS datapoints. Survey-weighted linear regression analyses were employed to assess the association between hypothyroidism and depression within the DS cohort, adjusting for demographic factors such as age, gender, and race. Results: This study found that individuals with DS exhibit a significantly higher prevalence of hypothyroidism (29.88%) compared to the general population (10.28%). Additionally, individuals with DS and comorbid hypothyroidism demonstrated a higher prevalence of depression (8.67%) compared to those without hypothyroidism (3.00%). These findings suggest a significant association between hypothyroidism and increased depression risk among individuals with DS. However, the overall prevalence of depression in DS (4.69%) remains substantially lower than in the general population (12.27%). Conclusions: This study highlights the importance of considering hypothyroidism as a potential contributor to depression in individuals with DS. Further research is needed to explore the underlying mechanisms of this association and potential screening and management strategies to address thyroid dysfunction and its potential psychiatric implications in DS. Full article

Background/Objectives: Primary malignant lung tumors in children are rare and diagnostically challenging. This study presents a single-center experience in the diagnosis and treatment of these tumors, emphasizing the role of histopathological and genetic profiling in informing individualized therapeutic strategies. Methods: We retrospectively reviewed records of seven pediatric patients (ages 2–18) treated from 2015 to 2025. Diagnostics included laboratory tests, chest CT, bronchoscopy, and histopathological/immunohistochemical analysis. Treatment primarily involved surgical resection, complemented by chemo-, radio-, or targeted therapies when indicated. Results: Inflammatory myofibroblastic tumor (IMT) represented the most commonly diagnosed entity (3/7 cases). The tumors presented with nonspecific symptoms, most frequently dry cough. Tumor type distribution was age-dependent, with aggressive forms such as pleuropulmonary blastoma predominantly affecting younger children, whereas IMT and carcinoid tumors were more common in older patients. Surgical resection remained the mainstay of treatment in the majority of cases. Bronchoscopy served as a valuable adjunct in the initial management of tumors exhibiting intraluminal growth, allowing for direct visualization, tissue sampling, and partial debulking to alleviate airway obstruction. In patients with an initially unresectable IMT harboring specific gene fusion rearrangement (e.g., TFG::ROS1), neoadjuvant targeted therapy with crizotinib enabled adequate tumor shrinkage to allow for subsequent surgical resection. Two patients in the study cohort died as a result of disease progression. Conclusions: A multidisciplinary diagnostic approach—integrating radiologic, bronchoscopic, histopathological, and genetic evaluations—ensures high diagnostic accuracy. While conventional treatments remain curative in many cases, targeted therapies directed at specific molecular alterations may offer essential therapeutic options for selected patients. Full article

Background: Copy number variants of uncertain significance (CNVus) from chromosome microarray analysis (CMA) presents unresolved challenges for clinical geneticists, genetic counselors, and patients. We performed a systematic reevaluation of reported CNVus and reanalysis of selected CNVus by whole genome sequencing (WGS) to assess the diagnostic value and clinical impact on CNVus reclassification. Methods: We retrospectively reviewed 5277 consecutive pediatric cases by CMA from the Yale Clinical Cytogenetics Laboratory over a 13-year period. Reevaluation was performed on all reported CNVus following current ACMG/ClinGen guidelines. Reanalysis by WGS was applied to selected cases for reclassification of CNVus. Results: A total of 567 CNVus from 480 cases were reported, which accounted for 9.1% of pediatric cases. A total of 4 CNVus in 4 cases (0.8%, 4/480) were reclassified to pathogenic/likely pathogenic CNVs (pCNVs/lpCNVs); while 23 CNVus in 23 cases (4.8%, 23/480) were reclassified to benign/likely benign CNVs (bCNVs/lbCNVs). The overall rate of reclassification was 5.6%. WGS performed on selected cases further defined breakpoints and ruled out additional causative genetic variants. Conclusions: The results from this study demonstrated the diagnostic value of periodic reevaluation of CNVus and reanalysis by WGS in an interval of 3–5 years and provided evidence to support standardized laboratory reevaluation and reanalysis. Full article

Background: Fanconi Anemia (FA) is a rare disorder, characterized by chromosomal instability, congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. FA is caused by pathogenic variants in any of the 23 (FANCA-FANCY) linked genes. Procedure: Retrospective analysis of 13 FA patients with a causative variant was performed. Patients (6 boys and 7 girls) aged from 9 to 26 years old, (mean age of 7.3 years), at diagnosis. Results: Phenotype evaluation demonstrated in 11/13 patients’ congenital anomalies, with pigmentary changes and short stature, present in 90% of cases. Hematological abnormalities were present in 10/11 patients, with thrombocytopenia being the prominent finding. Genetic analysis for the most common complementation group FA-A revealed that 12/13 patients belonged to this group and only one patient was found to be FA-E. Exon deletions, single nucleotide variations, and duplications were identified. Familial patterns, due to consanguinity, were evident in one case. Twelve patients underwent hematopoietic stem cell transplantation (HSCT), with variable pre-HSCT supportive treatments. Post-HSCT data showed that 9 out of 10 patients for whom follow up data was available, survived for a median time of 5.4 years. Complications like acute graft-versus-host disease were noted. Conclusions: Our study highlights the importance of genotype towards tailored monitoring for children and families with FA. Full article

Background: Pathological complete response (pCR) serves as a prognostic surrogate endpoint for long-term clinical outcomes in breast cancer patients receiving neoadjuvant systemic therapy (NAST). This study aims to develop and evaluate machine learning-based biomarkers for predicting pCR and recurrence-free survival (RFS). Methods: This retrospective monocentric study included 235 women (mean age 46 ± 11 years) with non-metastatic breast cancer treated with NAST. We developed various machine learning models using clinical features (age, genetic mutations, TNM stage, hormonal receptor expression, HER2 status, and histological grade), along with morphological features (size, T2 signal, and surrounding edema) and radiomics data extracted from pre-treatment MRI. Patients were divided into training and test groups with different MRI models. A customized machine learning pipeline was implemented to handle these diverse data types, consisting of feature selection and classification components. Results: The models demonstrated superior prediction ability using radiomics features, with the best model achieving an AUC of 0.72. Subgroup analysis revealed optimal performance in triple-negative breast cancer (AUC of 0.80) and HER2-positive subgroups (AUC of 0.65). Conclusion: Machine learning models incorporating clinical, qualitative, and radiomics data from pre-treatment MRI can effectively predict pCR in breast cancer patients receiving NAST, particularly among triple-negative and HER2-positive breast cancer subgroups. Full article

Background: Osteogenesis imperfecta (OI) is a rare genetic connective tissue disorder characterized by bone fragility, most often caused by pathogenic variants in type I collagen genes. In this context, we aimed to describe the clinical and epidemiological characteristics of patients with OI who were hospitalized for coronavirus disease (COVID)-19 in Brazil between 2020 and 2024. Methods: We conducted a retrospective descriptive analysis using data from the Brazilian Unified Health System (SUS, which stands for the Portuguese Sistema Único de Saúde) through the Open-Data-SUS platform. Patients with a confirmed diagnosis of OI and hospitalization due to COVID-19 were included. Descriptive statistical analysis was performed to evaluate demographic, clinical, and outcome-related variables. We included all hospitalized COVID-19 cases with a confirmed diagnosis of OI between 2020 and 2024. Results: Thirteen hospitalized patients with OI and COVID-19 were identified. Most were adults (9; 69.2%), male (7; 53.8%), self-identified as White (9; 69.2%), and all were residents of urban areas (13; 100.0%). The most frequent symptoms were fever (10; 76.9%), cough (9; 69.2%), oxygen desaturation (9; 69.2%), dyspnea (8; 61.5%), and respiratory distress (7; 53.8%). Two patients had heart disease, one had chronic lung disease, and one was obese. As for vaccination status, five patients (38.5%) had been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Four patients (30.8%) required admission to an intensive care unit (ICU), and six (46.2%) required noninvasive ventilatory support. Among those admitted to the ICU, only two required invasive mechanical ventilation. The clinical outcome was death in two cases (15.4%). Both patients were male, White, and had not been vaccinated against SARS-CoV-2. One was 47 years old, was not admitted to the ICU, but required noninvasive ventilation. Despite the underlying condition most patients had favorable outcomes, consistent with an international report. Conclusions: This is the first report to describe the clinical and epidemiological profile of patients with OI hospitalized for COVID-19 in Brazil, providing initial insights into how a rare bone disorder intersects with an acute respiratory infection. The generally favorable outcomes observed—despite the underlying skeletal fragility—suggest that individuals with OI are not necessarily at disproportionate risk of severe COVID-19, particularly when appropriately monitored. The occurrence of deaths only among unvaccinated patients underscores the critical role of SARS-CoV-2 vaccination in this population. Although pharmacological treatment data were unavailable, the potential protective effects of bisphosphonates and vitamin D merit further exploration. These findings support the need for early preventive strategies, systematic vaccination efforts, and dedicated clinical protocols for rare disease populations during infectious disease outbreaks. Full article

Background/Objective: Hypertrophic cardiomyopathy (HCM) often presents later in the disease course, with frequent misdiagnoses and population-level underdiagnoses. Underserved patients may have even greater diagnostic delays. We aimed to test the hypothesis in a retrospective cohort that artificial intelligence analysis of ECGs (AI-ECG) could have afforded the opportunity for earlier diagnosis of HCM in one health system. Methods: We collected all available ECGs from patients referred to an HCM Center of Excellence over 15 years, both before and after HCM diagnosis. We applied AI-ECG to each ECG in a blinded fashion to predict the probability of HCM. We calculated the time between each patient’s AI-ECG diagnosis and clinical diagnosis. We examined the sensitivity and specificity of AI-ECG for all patients, and by septal subtype and genetic test result. Results: 3499 ECGs were analyzed in 404 patients (age 56 ± 18 years, 52% female). AI-ECG correctly identified HCM in 155 patients with a sensitivity of 67%, specificity of 95%, positive predictive value of 94%, and a negative predictive value of 69%. The AUC was similar using mean probability from all ECGs for each patient (AUC 0.91 [0.88, 0.94]) or using probability from the first ECG (AUC 0.91 [0.87,0.93]). AI-ECG diagnosed 27 patients over 1 year before clinical diagnosis, and up to 16.3 years early. Black patients were more likely than White patients to have an AI-ECG diagnosis before a clinical diagnosis (p = 0.005). Conclusions: AI-ECG offers the potential for advanced HCM diagnosis. Differences in identification timing between subgroups highlight inequities in current care and show the potential of AI-ECG for the greatest benefit in underserved ethnic groups. Full article

Focal and segmental glomerulosclerosis (FSGS) describes a histological pattern of injury seen by light microscopy in kidney biopsy specimens and is the end result of various injuries to the podocyte. Our understanding of this disease entity has evolved greatly since it was first described, with particular focus on changes in the classification of FSGS as a disease entity and expansion in our understanding of the underlying pathophysiology. The incidence and prevalence of FSGS and FSGS-associated end-stage kidney disease (ESKD) have increased globally, particularly in the United States; it is now the most common primary glomerular disorder in those with ESKD. APOL-1 is likely responsible for this epidemiological trend in kidney disease in the US and is an important focus of clinical trials and potential targeted therapies. Currently, the goal of treatment in FSGS is to achieve remission of proteinuria and to prevent progression to ESKD. Remission is achieved by using immunosuppressive therapies in primary FSGS, but treatment in secondary and genetic FSGS is largely supportive. Recurrent FSGS (rFSGS) post-transplantation remains a significant clinical challenge to nephrologists; current monitoring and treatment strategies are based on retrospective meta-analysis and observational studies with no clear consensus as to the optimum approach. Emerging therapies are focused on developing more targeted interventions in genetic and secondary FSGS. This review article aims to comprehensively explore this multifaceted disease entity. Full article

Background: The national guidelines, informed by evidence from the National Institutes of Health (NIH), define the criteria for genetic testing of BRCA1/2 and other genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). When a germline pathogenic variant (PV) is identified in an index case, clinical recommendations advise informing at-risk relatives about the availability of predictive genetic testing, as early identification of carriers allows for timely implementation of preventive measures. Methods: This retrospective observational study examined data collected between 2017 and 2024 at the Medical Genetics Unit of the “Renato Dulbecco” University Hospital in Catanzaro, Italy. The analysis focused on trends in the identification of individuals carrying PVs in cancer predisposition genes (CPGs) and the subsequent uptake of cascade genetic testing (CGT) among their family members. Results: Over the study period, from 116 probands were performed 257 CGTs on 251 relatives. A notable reduction of approximately ten years in median age was observed, 39% were found to carry familial mutation and were referred to personalized cancer prevention programs. Among these, 62% accessed Oncological Genetic Counselling (CGO) within one year of the proband’s diagnosis, suggesting effective communication and outreach. Conclusions: The findings highlight the critical role of effective CGO and intrafamilial communication in hereditary cancer prevention. The identification of PVs, followed by timely CGTs and implementation of preventive strategies, significantly contributes to early cancer risk management. Periodic monitoring of CGT uptake and outcome trends, as demonstrated in this study, is essential to refine and optimize genetic services and public health strategies. Full article

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization. Full article

Background/Objectives: Intrachromosomal amplification of chromosome 21 (iAMP21) represents a rare and heterogeneous distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (ALL) initially associated with a poor prognosis. Treatment intensification with additional doses of methotrexate and asparaginase was associated with better treatment outcomes. Methods: In this retrospective single-center study, we evaluated the impact of iAMP21 on treatment outcome in a cohort of pediatric patients treated with an intensified asparaginase regimen and describe the genomic landscape of four patients with iAMP21. Results: Four out of 89 patients > 1 year old were classified as iAMP21 positive. Five-year event-free survival (EFS) was inferior in the iAMP21-positive group: 25% versus 85.6% (p = 0.001). The cumulative incidence of relapse and treatment-related mortality were 50% vs. 9.9% and 0% vs. 2.38%, respectively, in the iAMP21-positive and non-iAMP21 groups (p = 0.02 and 0.76, respectively). These results did not translate into a significant difference in overall survival: 100% vs. 93.7% (p = 0.6). The presence of iAMP21 (HR 7.68, 95% CI 2.04–29.05; p = 0.002) and a measurable residual disease ≥1% after induction on day +33 (HR 8.82, 95% CI 2.6–29.91; p = 0.001) retained significant negative impact on EFS in multivariate analysis. Conclusions: We found an independent significant prognostic impact of iAMP21 on EFS among pediatric patients with ALL, and clinical presentation and early treatment response did not classify these patients as HR. Diverse genetic backgrounds among iAMP21-positive patients might influence the treatment response and outcome of this heterogeneous disease. Full article