Search Results (1,771)

Genetic dystonias are a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions that cause repetitive movements and abnormal postures. Often beginning in childhood, they can significantly affect quality of life. Although individually rare, genetic causes are collectively relevant in pediatric dystonias, with over 250 associated genes. Among these, TOR1A, SGCE, and KMT2B are the most frequently reported in pediatric forms. Diagnosis is challenging due to the wide clinical and genetic variability. Recent advances in genetic testing, including whole-exome and whole-genome sequencing, have improved the early identification of causative variants. Functional data on selected mutations are helping to refine genotype–phenotype correlations. Management typically requires a multidisciplinary approach. Symptomatic treatments include anticholinergics, benzodiazepines, and botulinum toxin, while deep brain stimulation can be effective in refractory cases, especially in patients with TOR1A variants. Disease-modifying therapies are also emerging, such as gene therapy for AADC deficiency, highlighting the potential of precision medicine. This review provides an updated overview of pediatric genetic dystonias, with a focus on differential diagnosis and treatment strategies. Early and accurate diagnosis, together with personalized care, is key to improving outcomes in affected children. Full article

Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a cohort of patients from the Middle East and North Africa, both understudied and highly consanguineous populations. Whole exome sequencing (WES) was carried out on 81 patients and their family members at a tertiary center in Qatar. We found damaging mutations in half of the patients: 15 in known epilepsy genes, and 19 in contested or unknown genes. The mutations include single nucleotide polymorphisms (SNVs), frameshifts, copy number variations (CNVs), and loss of homozygosity (LOH). Fifteen of the SNVs are novel, and seventeen are homozygous, reflective of the characteristics of the cohort. In addition, we used the WES data to type HLA alleles for 13 class I and II genes. We show that DRB3*01:01:02G is negatively associated with epilepsy, in contrast to DRB4*01:01:01G, which may be a risk allele. In addition to expanding the knowledge base of genes involved in epilepsy, our findings show that genetic predisposition, inclusive of immune genes, suggests a complex etiology. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental impairment that occurs due to mutations related to the formation of the nervous system, combined with the impact of various epigenetic and environmental factors. This necessitates the identification of the genetic variations involved in ASD pathogenesis. We performed whole exome sequencing (WES) in a cohort of 22 Bulgarian male and female individuals showing ASD features alongside segregation analyses of their families. A targeted panel of genes was chosen and analyzed for each case, based on a detailed examination of clinical data. Gene analyses revealed that specific variants concern key neurobiological processes involving neuronal architecture, development, and function. These variants occur in a number of genes, including SHANK3, DLG3, NALCN, and PACS2 which are critical for synaptic signaling imbalance, CEP120 and BBS5 for ciliopathies, SPTAN1 for spectrins structure, SPATA5, TRAK1, and VPS13B for neuronal organelles trafficking and integrity, TAF6, SMARCB1, DDX3X, MECP2, and SETD1A for gene expression, CDK13 for cell cycle control, ALDH5A1, DPYD, FH, and PDHX for mitochondrial function, and PQBP1, HUWE1, and WDR45 for neuron homeostasis. Novel single nucleotide variants in the SPATA5, CEP120, BBS5, SETD1A, TRAK1, VPS13B, and DDX3X genes have been identified and proposed for use in ASD diagnostics. Our data contribute to a better understanding of the complex neurobiological features of autism and are applicable in the diagnosis and development of personalized therapeutic approaches. Full article

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder. Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population. Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10⁻⁸), NBPF10 (rs1553120233, p-value = 9.262 × 10⁻¹³), and NBPF16 (rs200632836, p-value = 1.04 × 10⁻⁶). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes. Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology. Full article

Inherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragile skin that blisters easily. Targeted therapies for EB necessitate personalized approaches, underscoring the importance of precise diagnostics through genetic analysis and skin biopsy using transmission electron microscopy and/or immunohistochemistry. This study highlights the application of whole-exome sequencing (WES) to identify key pathogenic variants associated with EB. Most identified variants were associated with the recessive form of dystrophic EB, including four novel COL7A1 mutations: p.Leu1488ArgfsTer222, c.7759-3C>G, p.Gln1886Ter, and c.6501+6T>C, as well as recurrent variants p.Lys142Arg and p.Gly2049Glu. Additionally, variants were detected in KRT5 (c.971T>C, p.Val324Ala), associated with EB simplex, and in LAMB3 (c.2500C>T, p.Gln834Ter) in the homozygous state, associated with junctional EB. In silico splice prediction tools suggested disrupted splicing in both cases. One patient received topical gentamicin therapy targeting the nonsense mutation p.Gln1886Ter. These findings underscore the utility of WES in EB diagnostics, broaden the mutation spectrum, and contribute to the understanding of genotype–phenotype correlations in adult patients with EB. Full article

The clinicopathologic and molecular features of serrated lesions with dysplasia in inflammatory bowel disease (IBD) remain poorly understood. We examined a total of 2396 patients treated for IBD at the University of Szeged between 2011 and 2023. Among them, 177 (7%) patients were diagnosed with colorectal neoplasia, of which only 11 (6%) had serrated dysplasia (n = 13). Of the 13 lesions, 5 (38%) showed features of sessile serrated lesion (SSL)-like dysplasia; 1 (8%) exhibited characteristics of traditional serrated adenoma (TSA)-like dysplasia; 6 (46%) were classified as serrated dysplasia, not otherwise specified (NOS); and 1 (8%) displayed mixed features of SSL-like and TSA-like dysplasias. At the time of the serrated dysplasia diagnosis, the mean age of the patients was 56 years. Ten (91%) patients had ulcerative colitis, and one (9%) had Crohn’s disease. Pancolitis was observed in seven (64%) patients. The mean duration of IBD at the time of the serrated dysplasia diagnosis was 26 years. Most lesions (n = 9; 69%) were found in the left colon, including SSL-like dysplasia (3/5; 60%) and serrated dysplasia NOS (5/6, 83%). Eleven (85%) lesions had a polypoid endoscopic appearance. The mean size of the serrated dysplasia was 0.8 cm. Most lesions (n = 8; 62%) showed low-grade dysplasia. Serrated dysplasia was often associated with conventional (n = 3; 27%) or nonconventional dysplasia (n = 3; 27%). During the follow-up, 5 (45%) of the 11 patients developed colorectal cancer, including 3 patients with serrated dysplasia NOS, 1 with SSL-like dysplasia, and 1 with TSA-like dysplasia. Whole-exome sequencing revealed that the SSL-like dysplasia harbored mutations in BRAF (p.V600E), MLH1, KRAS, PTEN, POLE, KMT2C, and/or EXT1, whereas the serrated dysplasia NOS showed mutations in TP53, POLG, BRAF (p.G469A), KMT2C, and/or EXT1. One patient with both SSL-like dysplasia and mixed SSL-like/TSA-like dysplasia carried a pathogenic MUTYH (p.R217H) mutation, along with mutations in MADD. Serrated dysplasia was rare in IBD, with a prevalence rate of 6%. The SSL-like dysplasia exhibited distinct clinicopathologic and molecular characteristics compared with its sporadic counterpart. Similarly, serrated dysplasia NOS displayed unique molecular features compared with SSL-like dysplasia and could carry a higher risk of malignancy. Full article

Objective: Ventriculomegaly is the main prenatal imaging feature for diagnosing fetal central nervous system anomalies in humans. Many ventriculomegalies can be related to genetic causes, regardless of their imaging presentations. Among these, MPDZ variants have been reported to cause severe ventriculomegaly inherited in an autosomal recessive manner (OMIM#615219). Several hypotheses have been put forward linking MPDZ variants to ventriculomegaly, but the precise underlying mechanisms, in particular whether its origin is obstructive or non-obstructive, are yet to be elucidated. Methods: To address this question, we retrospectively analyzed pre- and postnatal neuro-imaging and neuropathological data for cases of ventriculomegaly in which MPDZ variants were found through exome or genome sequencing. We performed anti-MPDZ immunostaining on fetal brain samples. Results: We analyzed six cases (four fetuses and two children) of ventriculomegaly of variable severities with MPDZ variants. The precise analysis of brain MRI data, corroborated by fetopathological examinations, demonstrated an obstructive pattern of ventriculomegaly upstream from partial fusion of the thalami, also called diencephalosynapsis, with partial atresia of the third ventricle, which could extend to Sylvius’s aqueduct. Conclusions: The morphological analysis using targeted brain magnetic resonance imaging (MRI) and neuropathological data allowed us to unravel the underlying mechanisms of congenital ventriculomegaly related to MDPZ variants. Full article

Background/Objectives: Joubert syndrome (JS, MIM 213300) is a rare genetic condition characterized by respiratory control disturbances, abnormal eye movements, ataxia, cognitive impairment, and the notable agenesis of the cerebellar vermis. The molar tooth sign visible in magnetic resonance imaging of the brain serves as a diagnostic tool for JS. Variants in the TCTN3 gene can lead to the development of several diseases, including JS type 18, Orofaciodigital syndrome IV, and Meckel–Gruber syndrome. Methods: We performed whole-exome sequencing (WES) in a 49-year-old woman with JS characterized by severe intellectual disability, ataxic gait, agenesis of the cerebellar vermis leading to the molar tooth sign, dystonic movements, strabismus, and nystagmus. Moreover, the patient also showed a thickened corpus callosum. Results: Molecular analysis through WES revealed the heterozygous variants c.182dup (p.G62Wfs*18) and c.1452+4del in the TCTN3 gene, expanding our understanding of the genetic diversity and potential phenotypic implications associated with TCTN3 variations. Conclusions: To our knowledge, this is the first patient with JS and a thickened corpus callosum. Moreover, a thickened corpus callosum has never been identified in patients with pathogenic variants of the TCTN3 gene. Full article

Background/Objectives: Brain arteriovenous malformations (bAVMs) are rare vascular anomalies characterized by direct connections between arteries and veins, bypassing the capillary network. This study aimed to identify potential genetic factors contributing to the development of sporadic bAVMs. Methods: Three patients (AVM1–3) from Kazakhstan who underwent microsurgical resection at the National Centre for Neurosurgery (NCN) in Astana, Kazakhstan, were analyzed. Brain AVMs were diagnosed using magnetic resonance imaging (MRI). Genomic DNA was isolated from whole venous blood samples, and whole-exome sequencing was performed on the NovaSeq 6000 platform (Illumina). Variants were filtered according to standard bioinformatics protocols, and candidate gene prioritization was conducted using the ToppGene tool. Results: In silico analysis further revealed candidate genes likely associated with lesion development, including COL3A1, CTNNB1, LAMA1, NPHP3, SLIT2, SLIT3, SMO, MAPK3, LRRK2, TTN, ERBB2, PARD3, and OBSL1. It is essential to focus on the genetic variants affecting the following prioritized genes: ERBB2, SLIT3, SMO, MAPK3, and TTN. Mutations in these genes were predicted to be “damaging”. Most of these genes are involved in signaling pathways that control vasculogenesis and angiogenesis. Conclusions: Defects in genes associated with ciliary structure and function may be critical to the pathogenesis of brain AVMs. These findings provide valuable insights into the molecular underpinnings of bAVM development, emphasizing key biological pathways and potential candidate genes. Further research is needed to establish robust correlations between specific genetic mutations and clinical phenotypes, which could ultimately inform the development of improved diagnostic, therapeutic, and prognostic approaches. Full article

DNA nanoball sequencing (DNBSEQ) is one of the most rapidly developing sequencing technologies and is widely applied in genomic and transcriptomic investigations. Recently, a new PE300 sequencing option primarily recommended for amplicon analysis was released for DNBSEQ-G99 and G400 devices. Given their unprecedentedly high data yield per flow cell, the new PE300 kits could be a great choice for various sequencing tasks, but we found that combining different types of DNA libraries in a single run could lead to undesired artifacts in the data. In this study, we investigate the occasional read cross-contamination that we first observed in our DNBSEQ PE300 run. The phenomenon, which we refer to as “software contamination”, is not actual contamination but primarily manifests as improper forward/reverse read pairing, improper demultiplexing, or as “digital chimeric” reads. Although rare, these artifacts were found in all runs we have analyzed, including several MGI demo datasets (both PE100 and PE150). In this study, we demonstrate that these artifacts arise primarily from the incorrect resolution of sequencing signals produced by neighboring DNA nanoballs, leading to mixing out forward and reverse reads or improper demultiplexing. The artifacts occur most frequently with read pairs where the length of insert sequence is shorter than the read length. Based on a few external NA12878 human exome sequencing data, we conclude that the total improper pairing rate in DNBSEQ data is comparable to Illumina ones. Overall, the problem only affects the analysis results when simultaneously sequenced libraries have markedly different insert size distribution or flow cell loading. Additionally, we demonstrate here that raw DNBSEQ data might contain ~2% optical duplicates, resulting from the same effect of close neighboring of DNB-sites in the flow cell. Full article

Background: Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has become a powerful diagnostic tool for rare genetic conditions. However, its success rate varies based on the underlying genetic etiology and the population studied. Methods: This retrospective study evaluated the diagnostic yield of NGS in a cohort of 137 pediatric patients with suspected rare genetic disorders in Bulgaria, a setting where such testing is not reimbursed and must be self-funded. The patients underwent either WES or targeted gene panel testing based on clinical presentation, family history, and genetic evaluation. Results: The overall diagnostic yield was 45.99%, with WES achieving 51.25% and targeted testing achieving 38.60%. The highest yield was observed in patients presenting with both dysmorphic features and neurodevelopmental delays (62.5%), while the lowest was observed among those with isolated neurodevelopmental issues (10%). A significant portion of the identified variants (35.9%) were novel. Eight patients were diagnosed with copy number variants (CNVs) detected only through WES. Conclusions: Our findings illustrate the value of WES as a first-line test and highlight the impact of deep phenotyping on diagnostic success. This study also emphasizes the need for a population-specific reference genome and equal access to genomic diagnostics in all European countries. Full article

Background: Colorectal cancer (CRC) remains one of the most prevalent and fatal malignancies globally, with radiotherapy playing a crucial role in the treatment of locally advanced rectal cancer (LARC). However, the efficacy of radiotherapy is limited by significant resistance, with only a small proportion of patients achieving a pathologic complete response (PCR) to neoadjuvant chemoradiotherapy (nCRT). This study aims to uncover the genetic and molecular factors contributing to radiotherapy resistance in CRC through an integrated analysis of germline mutations, transcriptomic data, and immune microenvironment characteristics. Methods: Whole-exome sequencing (WES) was performed on tumor samples from 12 LARC patients. Transcriptomic data from the TCGA-READ and GSE150082 (LARC with chemoradiotherapy) cohorts were integrated with WES findings. The independent cohort GSE190826 (neoadjuvant therapy in rectal cancer) dataset was utilized to validate the WES data. Single-cell RNA sequencing (scRNA-seq) analysis of GSE132465 (primary CRC) resolved cellular heterogeneity. A random forest algorithm was employed to develop a predictive gene signature. Results: Our findings reveal a mutational landscape associated with radiotherapy resistance, identifying specific germline mutations linked to treatment outcomes. Differential gene expression analysis highlighted pathways involved in DNA replication, DNA repair, and immune regulation, with a focus on the tumor immune microenvironment (TIME). A gene signature, including CDCA4, FANCA, PBRM1, RPL13, and C12orf43, was developed to predict radiotherapy response. Notably, CDCA4 expression was significantly associated with tumor mutation burden (TMB) and microsatellite instability (MSI), and it plays a crucial role in regulating B cell infiltration in the tumor microenvironment. Conclusions: Our study provides novel insights into the molecular mechanisms of radiotherapy resistance in CRC and proposes CDCA4 and B cell-related immune features as potential biomarkers for patient stratification and personalized treatment strategies. Full article

Rare autosomal recessive diseases are a major cause of mortality and morbidity. They occur more frequently in individuals with consanguineous parents, in which case the pathogenic variants are often located within regions of genetic identity by descent. A well-established and effective way of identifying these “autozygous” genomic regions has been to search for runs of homozygous genotypes in microarray SNP data. However, with the widespread use of whole-genome and exome sequencing in both diagnostic and research settings, it has become desirable to be able to both map autozygous regions and identify the deleterious variants using a single dataset. We have developed AgileMultiIdeogram, an application that can identify and visualize autozygous regions in inbred individuals using exome data as well as microarray SNP genotype data. This application has been successfully used in both research and diagnostic settings to map pathogenic mutations. Full article

Dysregulated expression of nuclear receptor superfamily 4 group A member 2 (NR4A2) has recently been associated with autistic spectrum disorder (ASD), speech impairment, and neurodevelopmental delay (NDD); however, its precise role in the prevalence and etiopathogenesis of ASD has not been fully elucidated. Herein, we aimed to explore the role of NR4A2 variants in the genetic underpinnings of ASD among Saudi children of different age ranges and phenotype severities. A total of 338 children with ASD from 315 unrelated families (293 simplex, 2 quads, and 1 quintet) were screened for NR4A2 variants via exome sequencing (ES) of the genomic DNA extracted from peripheral blood mononuclear cells (PBMCs), after which the probands with identified NR4A2 variants were further subjected to trio genetic analyses. ES analysis revealed 10 de novo NR4A2 variants (5 indels/nonsense, 2 missense, and 3 variants affecting splicing) in 8 unrelated probands (2.37%) and 2 affected siblings from 8 unrelated families (6 simplex (2.04%) and 2 quads (8.7%)). Three NR4A2 variants were notably recurrent among both affected and unaffected carriers. All identified indels and two splicing variants met the criteria for pathogenic/loss-of-function (LoF) variants according to the ACMG classification (PVS1), whereas the missense variants were classified as of uncertain significance (VUS). This study is among the first to identify such a high frequency of recurrent variants in an ASD cohort, suggesting their significant contribution to the etiopathogenesis of ASD within this population. Full article

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