Search Results (1,648)

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

Ménière’s Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in the Brazilian population. Although most MD cases are sporadic, familial MD (FMD) is observed in 5% to 20% of European cases. Through exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian individual with MD with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C, and chr11:17594108C>T, predicted to highly destabilize the protein structure. The manuscript aims to replicate genes previously reported in a Spanish cohort, and the main finding is that a Brazilian patient with MD also has variants previously reported in familial MD, supporting OTOG as the most frequently mutated gene in MD. Full article

Meckel–Gruber syndrome (MKS) is a rare autosomal recessive lethal ciliopathy, characterized by occipital encephalocele, cystic kidneys, and postaxial polydactyly, caused by mutations in different genes. Its significant genetic heterogeneity along with its clinical overlap with other ciliopathies makes early diagnosis essential for clinical management, accurate genetic counseling, and informing future reproductive decisions. Objectives: This study aims to describe a prenatally diagnosed case carrying a homozygous B9D1 variant and to examine the current literature on all variants reported in this gene associated with MKS. Methods: We comprehensively review the current literature on pathogenic B9D1 variants implicated in this syndrome. Additionally, we describe a case, presenting multiple congenital anomalies suggestive of MKS, genetically diagnosed by clinical exome sequencing on chorionic villi. Results: Occipital encephalocele and polycystic kidneys were revealed via ultrasound, thus suggesting MKS. Genetic testing identified the homozygous c.151T>C (p.Ser51Pro) variant in the B9D1 gene, inherited from healthy parents. Conclusions: This case supports the pathogenicity of the homozygous B9D1 c.151T>C variant and underscores the importance of timely prenatal assessment and targeted genetic testing for the detection of MKS risk in heterozygous subjects, enabling appropriate pregnancy management and informed reproductive choices. 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

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are dermal-based sarcomas that fall along a spectrum with different rates of local recurrence and metastasis. While AFX is less aggressive and confined to the dermis, PDS invades the subcutis. These tumors are most likely of mesenchymal origin, although they share common mutations with undifferentiated squamous cell carcinoma. Due to the rarity of these tumors, few studies have examined their molecular composition and gene expression. Initial studies, including exome and bulk RNA sequencing, targeted DNA sequencing of gene panels, DNA methylation, and copy number analyses, have identified recurrent UV-induced mutations in TP53, NOTCH, CDKN2A, and the TERT promoter. Recently, the first scRNA-seq dataset in AFX and PDS identified COL6A3 as a novel biomarker. In this review, we synthesize the above datasets and discuss our current understanding of the molecular drivers and prognostic biomarkers in these tumors. 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

Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by ataxia, sensory loss and pyramidal signs. While the majority of FRDA cases are caused by biallelic GAA trinucleotide repeat expansions in intron 1 of FXN, there is a subset of patients harboring a heterozygous pathogenic small variant compound-heterozygous with a GAA repeat expansion. We report on the diagnostic journey of a 21-year-old patient who was clinically suspected of having FRDA at the age of 12 years. Genetic testing included fragment analysis, gene panel analysis and exome sequencing, which only detected one pathogenic heterozygous missense variant (c.389 G>T,p.Gly130Val) in FXN. Although conventional repeat analyses failed to detect GAA expansions in our patient, subsequent short-read genome sequencing (GS) indicated a potential GAA repeat expansion. This finding was confirmed by long-read GS, which in addition revealed a complex pattern of interruptions. Both large and small GAA expansions with divergent interruptions containing G, A, GA, GAG and/or GAAG sequences were present within one allele, indicating mosaic sequence variations. Our findings underscore the complexity of repeat expansions which can exhibit both interruptions and somatic instability. We also highlight the utility of long-read GS in unraveling intricate genetic profiles, ultimately contributing to more accurate diagnoses in clinical practice. Full article

Psychosis constitutes a cardinal component of schizophrenia and affects nearly fifty percent of those with bipolar disorder. We sought to molecularly characterize psychosis segregating in consanguineous families. Participants from eight multiplex families were evaluated using standardized testing tools. DNA was subjected to exome sequencing followed by Sanger sequencing. Effects of variants were modeled using in-silico tools, while cDNA from a patient’s blood sample was analyzed to evaluate the effect of a splice-site variant. Twelve patients in six families were diagnosed with schizophrenia, whereas four patients from two families had psychotic bipolar disorder. Two homozygous rare deleterious variants in INSR (c.2232-7T>G) and NFXL1 (c.1322G>A; p.Cys441Tyr) were identified, which segregated with severe treatment-resistant psychosis/schizophrenia in two families. There were none, or ambiguous findings in the other six families. The predicted deleterious missense variant affected a conserved amino acid, while the intronic variant was predicted to affect splicing. However, cDNA analysis from a patient’s blood sample did not reveal an aberrant transcript. Our results indicate that INSR and NFXL1 variants may have a role in psychosis that requires to be investigated further. Lack of molecular diagnosis in some patients suggests the need for genome sequencing to pinpoint the genetic causes. 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