Search Results (1,303)

Background: Noonan syndrome (NS) is a relatively common RASopathy that can be associated with a variety of phenotypic and genotypic variations and potential long-term health consequences. Its most described prenatal ultrasound features in the first trimester are thickened nuchal translucency (NT) and dilated jugular sacs; while heart defects, polyhydramnios and facial dysmorphisms are its known manifestations in the second and third trimesters. Methods: We present two cases of NS with the prenatal ultrasound diagnosis of external hydrocephalus (EH) in the second trimester. Results: Case 1 had a normal first trimester scan and showed mild polyhydramnios, an echogenic intracardiac focus (EIF) in the left ventricle and pyelectasis in the second trimester in association with the EH. The whole exome sequencing (WES) confirmed a pathogenic variant in the SOS1 gene. Case 2 showed increased NT, agenesis of the ductus venosus (DV), single umbilical artery (SUA), an EIF in the right ventricle and an abnormal prefrontal space ratio (PSFR). By the 19th gestational week, EH appeared. The ambient and quadrigeminal cisterns were also slightly widened. The WES revealed a PTPN11 gene variant. Conclusions: The most reported sonographic features of NS are either non-specific or difficult to integrate into routine screening, requiring substantial experience. In our two cases, we detected EH in the second trimester, which is rarely described as a prenatal ultrasound diagnosis. To our current knowledge, this is the first case reported of EH in NS caused by an SOS1 gene variant and these are the first cases reported with the prenatal sonographic diagnosis of EH in NS. Full article

Myopathic Ehlers-Danlos syndrome (RmEDS) is an emerging hybrid phenotype that combines connective and muscle tissue abnormalities. It has been associated with variants of the COL12A1 gene, which are known as Ullrich congenital muscular dystrophy-2 (UCMD2; 616470) and Bethlem myopathy-2 (BTHLM2; 616471). Here, we report two splicing mutations of COL12A1 identified in three patients from two unrelated families who present a combination of joint hypermobility and axial, distal, and proximal weakness. The muscular strength of their neck and limb muscles was assessed at 4/5 (MRC); however, when measured with a myometer, the expected percentage by age and sex ranged from 35% to 40% for elbow flexion, 37% to 75% for knee extension, and was 50% for neck flexion. In addition to confirming the characteristic atrophy of the rectus femoris, we presented evidence of involvement of the neck and lumbar muscles through MRI and CT imaging. In vitro studies revealed filamentous disorganization and an altered pattern of collagen XII alpha 1 chain migration due to the skipping of exons 55 and 56 of collagen XII. Additionally, we review the myopathic involvement of COL12-RM in 30 patients across 18 families with dominant mutations and 15 patients from 13 families with recessive mutations. Full article

SEC31A-related neurodevelopmental disorder (Halperin–Birk syndrome) was recently identified in two siblings who shared the phenotype of profound developmental delay, structural brain defects, spastic quadriplegia with multiple contractures, seizures, dysmorphism, and optic nerve atrophy. Both patients died during childhood. In this study, we identified an additional patient who suffers from global developmental delay and seizures. Genetic analysis inclusive of whole exome and genome sequencing identified a homoallelic variant in the SEC31A (p.Cys453Trp). Various in silico classifiers predicted a deleterious effect of the replacement of cystein with tryptophan at the 453rd position. Protein–protein interaction (PPI) network analysis of SEC31A revealed high-confidence interactions with SEC13, SEC23A, and SEC23B, suggesting potential regulatory roles in these processes. Structural analysis of the SEC31A–SEC13 interaction and the Cys453Trp mutant in SEC31A predicted that the stability of coat protein complex II would be compromised. Our findings support the clinical correlation of SEC31A variants with neurodevelopmental disorder. Full article

Background and Objectives: Type 2 diabetes mellitus (T2DM) is a health problem all over the world due to its serious complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular diseases, and limb amputation. The risk factors for T2DM are environmental, lifestyle, and genetic. The genome-wide association studies (GWASs) have revealed the linkage of certain loci with diabetes mellitus (DM) and its complications. The objective of this study was to examine the association of genetic loci with diabetic nephropathy (DN) in the Saudi population. Materials and Methods: Whole exome sequencing (WES) and bioinformatics analysis, such as Genome Analysis Toolkit, Samtools, SnpEff, Polymorphism Phenotyping v2, and Sorting Intolerant from Tolerant (SIFT), were used to examine the association of gene variations with DN in 26 Saudi patients (18 males and 8 females). Results: The present study showed that there are loci that are probably linked to DM and DN. The genes showed variations that include COCH, PRPF31, PIEZO2, RABL5, CCT5, PLIN3, PDE4A, SH3BP2, GPR108, GPR108, MUC6, CACNA1D, and MAFA. The physiological processes that are potentially affected by these gene variations include insulin signaling and secretion, the inflammatory pathway, and mitochondrial function. Conclusion: The variations in these genes and the dysregulation of these processes may be linked to the development of DM and DN. These findings require further verification in future studies with larger sample sizes and protein functional studies. The results of this study will assist in identifying the genes involved in DM and DN (for example, through genetic counseling) and help in prevention and treatment of individuals or populations at risk of this disease and its complications. Full article

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon–intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein. Full article

Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are not cured with first-line chemoimmunotherapy, resulting in poor prognosis. Schmitz et al. classified DLBCL into four prognostic genetic groups using whole-exome sequencing. We applied a simplified approach using a targeted next-generation sequencing assay (Archer FusionPlex Lymphoma Assay) to analyze samples from 105 patients—53 with a progression-free survival (PFS) < 2 years (the “Relapse group”) and 52 with a PFS > 5 years (the “Remission group”) following first-line systemic treatment. Patients were classified according to Schmitz et al. into the following categories: “MCD” (MYD88^L265P and CD79B alteration), “N1” (NOTCH1 alteration), “BN2” (NOTCH2 alteration and BCL6 translocation), and “EZB” (EZH2 alteration and BCL2 translocation). The predictive value of this simplified genetic classification and of relevant clinical features were evaluated. The “Relapse group” included more patients classified as MCD and N1, while fewer were classified as EZB and BN2. Also, cell-of-origin (COO) characteristics and the size of N1 aligned with the classification of Schmitz et al. However, the limited sample size precludes definitive conclusions about the predictive value of our simplified approach. Additionally, male sex, B symptoms, and bone marrow involvement were associated with relapse. Therefore, these clinical features may be useful in predicting outcomes until an effective molecular classification is widely adopted. Full article

Objective: Epilepsy, a common neurological disorder marked by recurrent seizures often starting in childhood, has a complex etiology. Advances in high-throughput sequencing now confirm that 70–80% of cases have a genetic basis. Accordingly, this study aims to evaluate the clinical relevance of genetic variations detected through epilepsy panels and whole exome sequencing (WES) in pediatric-onset epilepsy patients. Methods: For this study, we enrolled a cohort of pediatric patients involving 205 subjects with a preliminary diagnosis of epilepsy. Targeted next-generation sequencing panels for epilepsy and whole exome sequencing was performed using the NextSeq 500 platform. The results were analyzed with the QIAGEN Clinical Insight bioinformatic platform and were further confirmed and approved by the Human Genome Mutation Database and ClinVar databases. Results: In this study, an epilepsy panel was conducted in 138 patients, and whole exome sequencing was performed in 67 patients. No clinically relevant variants were identified in 29 (21.0%) patients who underwent the epilepsy panel and 27 (40.3%) patients who underwent WES. Variants were detected in 128 different genes in the epilepsy panel group and in 54 different genes in the WES group, with the frequency of these variants limited to one or two patients. Significance: In both the epilepsy panel and WES groups, variants in sodium channel proteins, specifically in the SCN1A, SCN8A, and SCN9A genes, were found to have a high frequency. Collectively, these findings suggest that sodium channel proteins may play an important role in epilepsy. Full article

Ataxia-telangiectasia is a rare autosomal recessive disorder that is difficult to diagnose due to its unpredictable presentation. It is characterized by cerebellar degeneration, telangiectasias, immunodeficiency, frequent pulmonary infections, and tumors. Immune system abnormalities manifest as disruptions in both cellular and humoral immunity. The most common findings include decreased levels of immunoglobulin classes (IgA, IgM, IgG, and IgG subclasses) and a reduced number of T and B lymphocytes. A four-year-old girl was initially evaluated and treated for skin lesions that presented as crusts spreading across her body. She was monitored by a pulmonologist due to frequent bronchial obstructions. Over time, she developed bilateral scleral telangiectasia, saccadic eye movements, and impaired convergence. Her gait was wide-based and unstable, with truncal ataxia and a positive Romberg sign. Laboratory tests revealed decreased immunoglobulin G levels, subclass IgG4 levels, elevated alpha-fetoprotein, and a reduced number of T and B lymphocytes. Brain magnetic resonance imaging showed cerebellar atrophy. Whole-exome sequencing identified heterozygous variants c.1564-165del, p.(Glu5221lefsTer43), and c.7630-2A>C in the serine/threonine-protein kinase ATM (ataxia-telangiectasia mutated) gene, confirming the diagnosis of ataxia-telangiectasia. Following diagnosis, treatment with intravenous immunoglobulin replacement was initiated along with infection prevention and management. The goal of this case report is to raise awareness of the atypical initial presentation that may lead to a diagnostic delay. We emphasize the importance of considering ataxia-telangiectasia in the differential diagnosis, even when classical neurological signs are not yet evident. Full article

Background/Objectives: The prediction of cancer types is primarily reliant on driver genes and their specific mutations. The advancement in novel omics technologies has led to the acquisition of additional genetic data. When integrated with artificial intelligence models, there is considerable potential for this to enhance the accuracy of cancer diagnosis. As mutational signatures can provide insights into repair mechanism malfunctions, they also have the potential for more accurate cancer diagnosis. Methods: First, we compared unsupervised and supervised machine learning approaches to predict cancer types. We employed deep and artificial neural network architectures with an explainable component like layerwise relevance propagation to extract the most relevant features for the cancer-type prediction. Ten-fold cross-validation and an extensive grid search were used to optimize the neural network architecture using driver gene mutations, mutational signatures and topological mutation information as input. The PCAWG dataset was used as input to discriminate between 17 primary sites and 24 cancer types. Results: Overall, our approach showed that the most relevant mutation information to discriminate between cancer types is increased by >10% using the whole genome or intergenic and intronic genome regions instead of exome information. Furthermore, the most relevant features for most cancer types, except for two, are in the mutational signatures and not the topological mutation information. Conclusions: Informative mutational signatures outperformed the prediction of cancer types in comparison to driver gene mutations and added a new layer of diagnostic information. As the degree of information within the mutational signatures is not solely based on the frequency of occurrence, it is even possible to separate cancer types from the same primary site by the different relevant mutations. Furthermore, the comparison of informative mutational signatures allowed the cancer-type assignment of specific impaired repair mechanisms. Full article

Congenital heart disease (CHD) represents a prevalent group of structural cardiac anomalies often associated with alterations in key transcription factors including NKX2-5, TBX5, and, particularly, GATA4. GATA4 is a zinc finger transcription factor essential for regulating genes involved in cardiogenesis. Here, we report the identification of a novel heterozygous missense variant in GATA4 (NM_002052.5:c.907G>T, p.Gly303Trp) in a family with a history of CHD. The proband, exhibiting ventricular septal defect (VSD) and pulmonary stenosis, was referred for genetic evaluation after recurrent spontaneous abortions occurred in their partner. In addition, the mother of the proband has a history of atrial septal defect (ASD) with pulmonary stenosis, which suggests a familial inheritance pattern. Full article

Background/objective: Mucinous borderline tumors of the ovary (MBOTs) are characterized by their unique histological features and intermediate malignant potential; however, the factors underlying their molecular carcinogenesis and tumor biology remain largely unknown. Developing cell lines from these tumors presents an ongoing challenge. The purpose of this study is to establish MBOT cell lines and characterize their biological features. Methods: Epithelial cells were collected and purified from surgically removed MBOT samples and then stably maintained with an extended life span by overexpressing CyclinD1/CDK4 in combination with human telomerase reverse transcriptase. The characterization of resulting cell lines was defined by morphology, growth kinetics, functional analysis, whole-exome sequencing, and tumorigenicity in mice. Results: Two independent cell lines, HMucBOT-1 and HMucBOT-2, were successfully established from the tissues of a patient with an MBOT, with the latter showing more aggressive growth capacity. In the patient-derived xenograft model, HMucBOT-1 cells retained the original morphological characteristics of the MBOT, whereas HMucBOT-2 cells displayed a transition to mucinous carcinoma accompanying undifferentiated carcinoma, suggestive of dedifferentiated carcinoma. Genetic analysis of the original tumor sample and HMucBOT-2 cells revealed shared oncogenic mutations. However, KRAS amplification and certain copy number alterations were uniquely observed in the HMucBOT-2 cells. Conclusions: The above results indicate that HMucBOT-1 can serve as a preclinical model for investigating the biological behavior of and potential targeted therapies for human MBOTs, with HMucBOT-2 serving as a valuable tool for studying the heterogeneity and genetic diversity of this tumor and explaining the potential causes of treatment failure or relapse. Full article

Background: This paper will identify the potential genetic causes of multimorbidity associated with autosomal dominant congenital cataract (ADCC). Methods: Whole exome sequencing (WES) was performed on 13 individuals affected with ADCC. Subsequent bioinformatic analyses identified variants with deleterious pathogenicity scores. Results: Disease-causing variants were identified in 8 genes already linked to cataract (CHMP4B, CRYAA, CRYBA1, CRYGD, CYP21A2, GJA8, OPA1, and POMGNT1), but variants previously associated with systemic disorders were also found in a further 11 genes (ACTL9, ALDH18A1, CBS, COL4A3, GALT, LRP5, NOD2, PCK2, POMT2, RSPH4A, and SMO). All variants were identified via pipeline data analysis, prioritising rare coding variants using Kaviar and the Genome Aggregation Database. The following ADCC-associated non-ocular phenotypes were identified in four patients in the cohort: (i) Horner’s pupils, vaso-vagal syncope, and paroxysmal orthostatic tachycardia syndrome; (ii) reduced kidney function and high cholesterol; (iii) hypertension, high cholesterol, and kidney stones; and (iv) grade 1 spondylolysis. Conclusions: We report 11 novel genes identified in an ADCC patient cohort associated with systemic disorders found, along with 8 known cataract-causing genes. Our findings broaden the spectrum of potentially cataract-associated genes and their related lens phenotypes, as well as evidence multimorbidities in four patients, highlighting the importance of careful multisystem phenotyping following genetic analysis. Full article

Lung cancer remains as the leading cause of cancer mortality worldwide. However, while current evidence suggests the existence of genomic differences between populations, indicating different risk factors associated with population-level genetic backgrounds, most studies have concentrated on populations of European ancestry, and more research is needed on non-European populations. We analyzed whole-exome sequencing data from 25 Mexican lung adenocarcinoma patients and compared them with a TCGA-PanCancer cohort enriched with patients of European ancestry as reference. Clinically relevant germline variants in cancer susceptibility genes are more frequent in our cohort (32% vs. 6.4%) than in the reference. Several mutational signatures (SBS32, SBS85, SBS12, SBS19) occurred at significantly higher frequencies in the Mexican cohort compared to the reference (p < 0.0001). Interestingly, the smoking-associated signature SBS4, present in 67.6% of smokers in the reference cohort, was absent in smoking Mexican patients (p < 0.01656). Somatic variant frequencies in SLC36A4 (20%; p < 0.00002), AP1S1 (8%; p < 0.00002), and TP53 (16%; p = 0.00005) showed significant differences from the European reference cohort. We demonstrate that all these observed biases were independent of the sample size. This study uncovers distinct genomic biases in lung cancer carcinogenesis in this population, compared to a European ancestry reference population, suggesting implications for precision medicine strategies in Latin American populations. Full article

Background and Objectives: Identifying carriers of Pathogenic/Likely Pathogenic Variants in patients with dementia is crucial for risk stratification, particularly in individuals with a family history. This study developed and validated a clinical prediction model using whole-exome sequencing-confirmed cohorts. Methods: A total of 601 Chinese patients with dementia and a family history were enrolled at Peking Union Medical College Hospital, with 476 in a retrospective derivation cohort and 125 in a temporal validation cohort. Predictive factors included age at onset, APOE ε4 status, and family history characteristics. Model performance was assessed using discrimination and calibration metrics. Results: In the derivation cohort (median age at onset 66 years), 10.3% carried Pathogenic/Likely Pathogenic Variants. Among patients with dementia, those with age at onset < 55 years (OR 2.56, p = 0.0098), more than two affected relatives (OR 3.32, p = 0.0039), parental disease history (OR 4.72, p = 0.015), and early-onset cases in the family (OR 2.61, p = 0.0096) were positively associated with Pathogenic/Likely Pathogenic Variant carriage, whereas APOE ε4 carriage was inversely associated (OR 0.36, p = 0.0041). The model achieved an area under the curve of 0.776 (95% CI, 0.701–0.853) in the derivation cohort and 0.781 (95% CI, 0.647–0.914) in the validation cohort (median age at onset 58 years), with adequate calibration. Conclusions: This model demonstrated strong predictive performance for Pathogenic/Likely Pathogenic Variant carriage, supporting its clinical utility in guiding genetic testing. Further research is needed to refine the model. Full article

Epilepsy is a prevalent neurological condition, having a wide range of phenotypic traits, which complicate the diagnosis process. Next-generation sequencing (NGS) techniques have improved the diagnostics for unexplained epilepsies. Our goal was to evaluate the utility and impact of genetic testing in the clinical management of pediatric epilepsies. In addition, we aimed to identify clinical factors that could predict a genetic diagnosis. This was a retrospective study of 140 pediatric patients with epilepsy with or without other neurological conditions that underwent NGS testing (multigene panel, WES = whole exome sequencing and/or WGS = whole genome sequencing). A comparison between genetically diagnosed versus non-diagnosed children was performed based on different clinical features. Univariate and multivariate logistic regression analysis was performed to identify clinical predictors of a positive genetic diagnosis. Most children underwent gene panel testing, while 30 had exome sequencing and 3 had genome sequencing. The overall diagnostic yield of genetic testing was 28.6% (40/140) for more than 28 genes. The most frequently identified genes with causative variants were SCN1A (n = 4), SCN2A (n = 3), STXBP1 (n = 3), MECP2 (n = 2), KCNQ2 (n = 2), PRRT2 (n = 2), and NEXMIF (n = 2). Significant predictors from the logistic regression model were a younger age at seizure onset (p = 0.015), the presence of intellectual disability (p = 0.021), and facial dysmorphism (p = 0.049). A genetic diagnosis led to an impact on the choice or duration of medication in 85% (34/40) of the children, as well as the recommendation for screening of comorbidities or multidisciplinary referrals in 45% (18/40) of children. Epilepsy is a highly heterogeneous disorder, both genetically and phenotypically. Less than one third of patients had a genetic diagnosis identified using panels, exomes, and/or genomes. An early onset and syndromic features (including global developmental delay) were more likely to receive a diagnosis and benefit from optimized disease management. Full article