BACKGROUND:Copy number variations (CNVs) in the 16p11.2 region are associated with neurodevelopmental disorders, but they exhibit incomplete penetrance and variable expressivity. Prenatal diagnosis of these CNVs presents significant challenges because of the unpredictable phenotypic outcomes. MATERIALS AND METHODS:We retrospectively analyzed two fetal cases diagnosed prenatally via amniocentesis with CNV sequencing (CNV-seq) as having 16p11.2 CNVs, and discussed them in the context of current literature. In this research, GTG-banding karyotype analysis, CNV-seq, and whole-exome sequencing were performed. RESULTS:Case 1 had a de novo 16p11.2 microdeletion [del(16)(p11.2)] accompanied by an ultrasound soft marker (absent nasal bone); the pregnancy was terminated after genetic counseling. Case 2 carried a de novo 16p11.2 microduplication [dup(16)(p11.2)] and was born with a normal phenotype to date. CONCLUSION:16p11.2 microdeletion and microduplication syndromes exhibit significant phenotypic heterogeneity and incomplete penetrance. When such CNVs are identified prenatally, integrated management - including parental testing, detailed fetal imaging, and comprehensive, nondirective genetic counseling - is essential to provide families with individualized risk assessment and support informed decision-making.
OBJECTIVE:This study aimed to investigate the causal associations and potential mechanistic pathways involving pulse rate, neuronal cell adhesion molecule (NrCAM), migraine, and other neurological disorders within the context of the glymphatic system. METHODS AND RESULTS:Using bidirectional two-sample Mendelian randomization analysis, we constructed simple, parallel, and serial causal pathway diagrams based on significant genetic evidence, in combination with a disease network approach, to elucidate key relationships and plausible biological routes. Key findings indicate that pulse rate influences NrCAM expression, and NrCAM mediates the development of migraine. Neurological disorders such as stroke and Parkinson's disease were found to impact related molecular pathways. The study identifies NrCAM as a pivotal molecule in the glymphatic system, influenced by lifestyle factors and contributing to migraine pathogenesis. Moreover, pulse rate acts as an initiating factor driving molecular changes, with neurological disorders serving as mediators in the causal network. CONCLUSION:The complex interplay between lifestyle, physiological factors, molecular mediators, and neurological disorders reveals an intricate network of causality in neurological disease. These findings underscore the importance of optimizing glymphatic function and highlight NrCAM as a potential therapeutic target. Understanding these interactions provides insights for developing targeted interventions and personalized treatment strategies for neurological disease prevention and management.
INTRODUCTION:Bipolar disorder is a mental disorder associated with extreme mood shifts. Psychosis (hallucinations, delusions, and thought disorder) can also co-occur in some patients. Although highly heritable, the genetic etiology of bipolar disorder remains unclear. METHODS:We visited outpatient departments of mental hospitals and recruited all members of a consanguineous family in which multiple siblings had psychosis. Clinical assessments using standardized rating tools were administered. Whole-exome sequencing was performed for all participants. RESULTS:Three male siblings were identified to have bipolar disorder with psychosis, while their sister was affected with bipolar disorder without psychosis. Other relatives were unaffected. Analysis of exome data identified six variants segregating with psychosis. Only one hemizygous variant, Bruton's tyrosine kinase ( BTK ) c.410A>G, p.(Asp137Gly), was predicted deleterious. The variant was rare in all publicly available databases (gnomAD allele frequency = 0.00001094) and was absent from the DNA of at least 400 unrelated ethnically matched controls. The amino acid affected by this variant was conserved among orthologs. The mutated BTK p.Gly137 residue was predicted to lack the interacting bond with p.Ser136. DISCUSSION:Most reported BTK variants are known to cause agammaglobulinemia. A de-novo variant in BTK p.(Arg255Gln) was previously associated with schizophrenia in one female patient. Multigenic deletions, including BTK , can cause deafness-dystonia-optic neuropathy syndrome, sometimes accompanied by psychosis. Taken together, these studies indicate that BTK may have a role in some mental disorders that needs to be investigated further. Use of animal models may elucidate any BTK function in the brain.
Schizophrenia is a chronic mental disorder characterized by abnormal synaptic connectivity. N-methyl- D -aspartate receptors (NMDARs) are essential for synaptic transmission and plasticity, and rare variants in the genes encoding NMDARs are linked to neurodevelopmental disorders. In this study, we examined rare pathogenic mutations in four GRIN2 genes, which encode the NMDAR subunit 2, in patients with schizophrenia using ion semiconductor technology and PCR-based fluorescence-based cycle sequencing. We identified 10 novel ultra-rare missense mutations in the GRIN2 genes, none of which were found in the GnomAD_genomes and the Taiwan BioBank. These findings suggest that ultra-rare pathogenic mutations may be present in some individuals with schizophrenia, supporting the existence of rare coding variants of synapse-associated genes that contribute to the genetic architecture of schizophrenia. Future research should explore the in-vitro and in-vivo effects of the identified mutations on the pathophysiology of schizophrenia for further insights.
Background Postpartum depression (PPD) is a prevalent mental health condition following childbirth, currently diagnosed primarily through subjective evaluations, and its underlying biological mechanisms remain poorly understood. Objectives This study evaluated the potential of miR-218-5p as a biomarker for PPD, while further explored its regulatory roles in depressive-like behaviors, inflammatory, and oxidative stress to provide clinical guidance for the precise diagnosis and treatment. Methods This study enrolled 106 PPD patients and 95 healthy puerperae. A PPD-like model was established in rats via chronic unpredictable mild stress (CUMS), with miR-218-5p overexpression in the experimental group. miR-218-5p levels were quantified via quantitative PCR. Receiver operating characteristic curve and logistic regression assessed miR-218-5p’s diagnostic and predictive value. In addition, standard animal behavioral tests evaluated behavioral alterations in the CUMS and miR-218-5p overexpression groups. ELISA measured changes in inflammatory cytokines and oxidative stress markers. Results In PPD patients, serum miR-218-5p were significantly lower and inversely related to depressive severity. It showed strong diagnostic accuracy for PPD and served as a standalone biomarker for predicting PPD onset. In CUMS rat model, key behaviors were distinctly altered. In addition, miR-218-5p expression was reduced in rat serum and hippocampus; hippocampal proinflammatory cytokine levels were increased, while antioxidant enzyme activity was lower. Overexpressing miR-218-5p in the model significantly alleviated depressive-like behaviors and reduced hippocampal inflammatory responses and oxidative stress injury. NRAS was a potential target gene of miR-218-5p. Conclusion miR-218-5p may act as a promising biomarker for PPD. It can reduce depressive-like symptoms via regulating inflammatory processes and rebalancing oxidative stress through NRAS .
We describe a rare familial occurrence involving two brothers: one diagnosed with autism spectrum disorder (ASD), and the other with a postnatally confirmed 47 XYY karyotype exhibiting autistic traits below the diagnostic threshold. The younger sibling met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Level 3 criteria, with prominent deficits in communication and behavior. The older sibling, though not fully meeting ASD criteria, showed borderline cognitive abilities, attentional difficulties, and limited social reciprocity. Both received individualized education and pharmacologic support. This case raises questions about Y chromosome dosage effects in neurodevelopment, particularly the role of Y-linked genes such as NLGN4Y. The co-occurrence of ASD and XYY-related traits within the same family highlights the possibility of a shared vulnerability and adds to the sparse literature on male-specific genetic influences. Early screening and multidisciplinary interventions may benefit at-risk siblings, even in the absence of full syndromic presentation.
BACKGROUND:A potential genetic link between inflammatory bowel disease (IBD) and educational attainment has been suggested. Understanding the underlying mechanisms of this genetic relationship is crucial for advancing the knowledge of their co-occurrence patterns. METHODS:Using genome-wide association study data for both IBD and educational attainment, a multiphase analytical approach was applied to examine their genetic correlation. The study involved three phases: first, linkage disequilibrium score regression and high-definition likelihood models were used to assess genome-wide genetic correlation; second, SUPERGNOVA was employed to analyze the genetic structure across specific chromosomal regions; and third, conditional/conjunctional false discovery rate (cond/conjFDR) methods were applied to measure genetic overlap and identify shared genetic loci between the two traits. RESULTS:The genome-wide analysis revealed significant genetic correlations between IBD, especially Crohn's disease, and educational attainment, while the association with ulcerative colitis was weaker. Regional analyses identified localized genetic correlation signals across several chromosomal regions between these traits. The application of the conjFDR framework confirmed the presence of overlapping genetic components, leading to the identification of key genetic variants contributing to disease susceptibility and progression. CONCLUSION:This genetic study provides new theoretical insights into the association between IBD and educational attainment, contributing to a deeper understanding of the mechanisms underlying their co-occurrence.
Turner syndrome, also referred to as congenital ovarian hypoplasia syndrome, is the most common sex chromosomal abnormality found in females. It results when one of the X chromosomes is missing, partially or completely. About half of the population with Turner syndrome have monosomy X (45,XO). The other 50% of the population has a mosaic chromosomal component (45,XO with mosaicism). The phenotype of patients with mosaic Turner syndrome may vary depending on the different mosaicism ratios. In this research, we provide a detailed description of three patients with low-level mosaic Turner syndrome. Combination of karyotype analysis, copy number variation sequencing, fluorescence in-situ hybridization, prenatal ultrasound, and genetic counseling is helpful for the prenatal diagnosis of mosaic Turner syndrome.
BACKGROUND:Autism spectrum disorder (ASD) has a complex genetic etiology, with limited data from Indian populations. This study delineates the genetic architecture of ASD in Indian children using whole exome sequencing (WES) and exploratory genetic association studies (GASs). METHODS:WES was performed on 142 Indian children with ASD, diagnosed per the Diagnostic and Statistical Manual V criteria. GAS compared cases to 180 age- and ethnicity-matched Indian controls (aged 4-8 years) who exhibited normal neurological development. Variants were annotated using annotate variation, classified per the American College of Medical Genetics and Genomics guidelines, and analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes pathways, and GAS associations. Chromosomal microarray 750K was used to confirm the copy number variations. RESULTS:WES identified pathogenic/likely pathogenic variants in 20 cases (14.08%) (12 autosomal dominant, five autosomal recessive, and three X-linked) and variants of uncertain significance in 107 cases (75.35%). Chromosomal microarray analysis revealed six pathogenic variants in 49 autism cases. Functional enrichment implicated neurotransmitter function, synaptic transmission, chromatin remodeling, and glutamatergic/GABAergic imbalances. GAS revealed significant variants (rs2014562 and rs7730228) and a chromosome 11 hotspot ( MUC6 , ZDHHC13 , OR8U1 , OR9G1 ), with chr5 : 130-131 Mb single nucleotide polymorphisms (SNPs) interacting with ADAMTS19 . CONCLUSION:This study highlights genetic heterogeneity in Indian ASD cases, identifying novel variants and pathways of potential biological relevance. Moderate GAS sample size and high variants of uncertain significance burden warrant further validation.
BACKGROUND:Copy number variants are an important source of normal and pathogenic genome variations. Constitutional deletions involving the distal part of the short arm of chromosome 12(12p13.33p13.32) are very rare. These deletions are associated with an emerging condition associated with variable phenotype, including a specific speech delay sound disorder, labeled childhood apraxia of speech, intellectual disability, and neurobehavioral problems. Trisomy of distal chromosome 15q has rarely been reported. It is generally believed that the terminal duplication of 15q26.2q26.3 is related to overgrowth phenotype, distinct facial features and intellectual disability. MATERIALS AND METHODS:A 21-year-old woman (gravida 1, para 0) underwent amniocentesis at 26 weeks' gestation following the detection of a persistent left superior vena cava of the fetus on prenatal ultrasound. In this research, GTG-banding karyotype analysis, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and fluorescence in-situ hybridization (FISH) were performed. RESULTS:CMA detected a 4.36 Mb deletion on chromosome 12p13.33p13.32 and a 7.59 Mb duplication on chromosome 15q26.2q26.3 of the fetus. No abnormality was found in the parents' genetic examination. After genetic counselling, the parents decided to continue the pregnancy. CONCLUSION:We provide a detailed description of the prenatal diagnosis and genetic counselling of a rare de-novo 12p13.33p13.32 deletion and 15q26.2q26.3 duplication in a Chinese family. A combination of karyotype analysis, CMA, WES, FISH, prenatal ultrasound, and genetic counselling is helpful for the prenatal diagnosis of chromosomal deletions/duplications and pathogenic gene variants.
OBJECTIVE:MicroRNAs exhibit remarkable potential as biomarkers due to their multiple advantages in Alzheimer's disease (AD). This study aimed to explore the significance of miR-484 in AD. METHODS:The study included 216 participants [70 healthy controls (HCs), 77 AD with nondepression, 69 AD with depression (AD-D)]. PCR measured serum and tissue miR-484 levels. Receiver operator characteristic curves evaluated miR-484 diagnostic potential for AD/AD-D. Logistic regression identified AD-D risk factors. Bioinformatics predicted miR-484 targets and functional pathways. Dual-luciferase assay validated the interaction between miR-484 and platelet derived growth factor subunit A (PDGFA). Chronic restraint stress (CRS) induced depression animal model by Kunming mice (20 each group × 6 groups). The effect of miR-484/PDGFA axis on depression-like behaviors was evaluated through behavioral tests (sucrose preference, forced swim, and open field). RESULTS:Serum miR-484 was downregulated in AD and further decreased in AD-D compared with HCs. MiR-484 downregulation diagnosed AD-D from AD. MiR-484 expression was correlated with amyloid β -protein 1-42 ( r = 0.682), total tau ( r = -0.575), Mini-Mental State Examination score ( r = 0.593), and Hamilton depression rating scale score ( r = -0.709). MiR-484 was a risk factor for depression in AD. In the depression mouse model, miR-484 overexpression ameliorated depression-like behaviors (sucrose preference, forced swim immobility time, locomotor activity) by regulating PDGFA. CONCLUSION:Downregulated miR-484 expression, correlating with cognitive function and depression degree, showed a diagnostic value on AD and AD-D. MiR-484 attenuated the CRS-induced depression-like behavior by regulating PDGFA.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication, as well as restricted and repetitive behaviors. Although ASD often manifests during early childhood, many individuals are diagnosed later in life due to difficulties in meeting increasing social demands. Early diagnosis and personalized treatment are crucial in lifetime ASD symptom trajectories. We report the case of a 27-year-old woman diagnosed with ASD in adulthood, in correlation with elevated homocysteine (Hcy) levels due to homozygosity for the MTHFR C677T polymorphism, whose symptoms deteriorated, possibly related to dietary changes. Following Hcy blood levels normalization, autistic symptoms of social interaction improved. This case highlights a potential relationship between environmental factors, such as dietary changes, and the late diagnosis of ASD, supporting the theory that interaction between environment and genetics, possibly, plays a role in ASD development.
OBJECTIVES:The catalytic subunit of NatA, the main component of the N-terminal acetyltransferase complex, which is involved in most of the acetylation of the human proteome, is encoded by the NAA10 gene. Mutations in the NAA10 gene lead to neurodegenerative diseases associated with disruption of acetylation. Ogden syndrome (OS) is a rare X-linked recessive or dominantly inherited disorder associated with NAA10 gene mutations, characterized by variable findings such as autism spectrum disorder, intellectual disability, and cardiac anomalies. In this article, it is aimed to clarify the functionality of two novel NAA10 gene variants in two female patients with OS. METHODS:A whole-exome sequencing (WES) study was performed from the blood samples of the patients. The effects of the two variants found by tertiary structure modeling, protein stability analysis, and molecular docking analyses on NAA10 were examined. RESULTS:Autism, intellectual retardation, and epilepsy were prominent in the patients, and heterozygous variants c.346C>T and c.439A>T in the NAA10 gene were detected in WES. The clinical findings were compatible with OS. The p.Arg116Trp and p.Met147Leu changes in the NAA10 gene caused changes in the overall topological structure of NAA10, including the substrate and ligand binding site. CONCLUSION:In this study, c.346C>T and c.439A>T variants were found to alter the functional stability, structure, and energy of NAA10. Functional analyses of NAA10 variants in two rare OS patients have once again demonstrated that novel variants are essential studies for phenotype-genotype correlation association steps.
BACKGROUND:Epidemiological evidence suggests a link between schizophrenia (SCZ) and increased breast cancer (BC) risk, but the genetic mechanisms remain unclear. Exploring their shared genetic susceptibility may help reveal the basis of this comorbidity. METHODS:This study was conducted utilizing genome-wide association study (GWAS) data for SCZ and BC, employing a multitiered genetic analytical framework to systematically assess the genetic association patterns between these two conditions. Initially, linkage disequilibrium score regression and high-dimensional likelihood modeling were applied to quantitatively evaluate genome-wide genetic correlations, while localized variant association analysis was performed to detect regional genetic association signals within specific genomic loci. Subsequently, conditional/conjunctional false discovery rate (condFDR/conjFDR) methodologies were implemented to uncover the shared genetic architecture underlying both traits. Ultimately, conjFDR was integrated with multitrait analysis of GWAS (MTAG) strategies to further identify and validate potentially overlapping genetic variant loci. RESULTS:The analysis revealed significantly positive genome-wide genetic correlations between SCZ and BC, as well as among various BC subtypes. Regional genetic structure analysis identified numerous chromosomal loci exhibiting shared genetic signals. The condFDR/conjFDR models provided additional confirmation of the genetic overlap between the two traits. Through the combined application of conjFDR and MTAG, a collection of shared genetic loci with plausible biological relevance was identified and substantiated, including BATXN7, FOXP1, EMB, LINC00536, ZNF365, MAPT, STXBP4 , and GATAD2A . CONCLUSION:The findings elucidated genetic associations between SCZ and BC and identified critical shared genetic contributors, thereby offering molecular evidence for the investigation of comorbidity mechanisms and potential intervention strategies.
OBJECTIVE:Deficits in social communication and social interaction are core features of autism spectrum disorder (ASD), and studies suggest that loneliness and social isolation are common. ASD has a strong genetic basis, but the genetic architecture and overlap with social phenotypes are not clear. METHODS:We analyzed summary statistics from genome-wide association studies on ASD (46 350), loneliness (452 302), and social isolation (288 950), using linkage disequilibrium score regression, local analysis of covariant annotation (LAVA), bivariate causal mixture model (MiXeR), and the conditional/conjunctional false discovery rate (cond/conjFDR). RESULTS:For ASD and social isolation, we found nonsignificant global genetic correlation ( rg = 0.02, P = 0.8), but LAVA identified 72 genomic regions with bidirectional correlations, and MiXeR estimated that 8.7 k of 13.1 k variants (81%) were shared, of which 53% had concordant effect directions. For ASD and loneliness, we found a positive genetic correlation ( rg = 0.26, P = 2e-10), LAVA identified 80 genomic regions with bidirectional genetic correlations, and MiXeR suggested that at least 3.8 k variants were shared. We identified nine specific shared genetic loci between ASD and loneliness and eight between ASD and social isolation (conjFDR < 0.05). Of these, 12 loci were novel for ASD. Genes mapped to these loci are involved in γ-aminobutyric acid (GABA), glutamate, calcium, and stress hormone signaling, cerebral glucose transport, TAU-accumulation, and immune function. CONCLUSION:We found extensive overlap in genetic architecture between ASD, loneliness, and social isolation, with bidirectional effects. By leveraging data for ASD and social traits, we identified 12 novel ASD related genetic loci implicating several genes, thereby elucidating potential pathways underlying their shared genetic architecture.
OBJECTIVE:Developmental and epileptic encephalopathy 9 (DEE9) is an X-linked genetic disorder characterized by the onset of seizures during infancy. Mutations in protocadherin 19 ( PCDH19 ) are the main cause of DEE9. Our study aims to demonstrate the diagnostic process and long-term follow-up of a female pediatric case presenting with recurrent seizures. METHODS:In the present study, a female child presented with recurrent epileptic seizures and findings of abnormal synchronous discharges on electroencephalograms. Whole exome sequencing (WES) was performed on the proband and her parents to identify potential genetic variants. RESULTS:A heterozygous variant (NM_001105243: c.695A>G) in PCDH19 was identified and validated using Sanger sequencing. Based on clinical features and genetic analyses, the patient was diagnosed with PCDH19 -female limited epilepsy. Furthermore, a 4-year follow-up was conducted to assess the impact of the pathogenic variant on phenotype and treatment outcomes. The patient exhibited normal intelligence, which differed with the clinical features reported in other studies involving the same variant. CONCLUSION:WES confirmed the diagnosis of DEE9, and subsequent follow-up highlighted the effectiveness of the treatment. Therefore, genetic testing can improve the diagnosis of DEE9, particularly in cases with atypical symptoms, and provide valuable insights for genetic counseling and clinical treatment strategies.
Despite drastic advances in psychiatric genetics, comparatively little attention has focused on the translation of those discoveries into real-world impact. This paper reviews the processes and considerations for integrating new techniques into clinical practice and provides an overview of areas of medicine where polygenic scores (PGS) are already being incorporated. We evaluate current PGS across three areas of psychiatry (depression, substance use disorders, and schizophrenia) against the criteria used by the National Electronic Medical Records and Genomics consortium to select PGS to study in a clinical context, finding that the PGS for psychiatric conditions are comparable to the PGS being implemented in clinical practice for other medical conditions. We conclude by discussing next steps for evaluating psychiatric PGS for clinical implementation including ethical issues that must be considered, and the need for more research on clinical utility to evaluate whether and how PGS can be used to improve behavioral health outcomes.
Genomic medicine has progressed rapidly, and many high-risk genetic variants for neuropsychiatric disorders have now been identified. However, clinical genetic testing is rarely utilized in psychiatric settings. This scoping review examined European clinical practice guidelines (CPGs) for genetic testing in neuropsychiatric disorders to map recommendations and identify gaps. Seventeen CPGs published since 2010 met the inclusion criteria. There was a wide variation in scope, quality, and conditions covered. Seven CPGs addressed autism spectrum disorder, generally recommending testing when additional features such as intellectual disability or dysmorphology were present. One CPG covered the investigation of intellectual disability, advising Fragile X testing, chromosomal microarray, and whole-genome sequencing. Most CPGs (11/17), related to dementia, advising testing with very early onset and/or an indicative family history. Overall, European CPGs for genetic testing in psychiatry vary significantly, contributing to clinician uncertainty. Harmonizing evidence-based CPGs is crucial to advance the integration of genetic testing in psychiatric practice.
BACKGROUND:Mood swings and irritable bowel syndrome (IBS) are closely related. However, the reason for the clinical concurrence of this phenomenon is unknown, and maybe it is because the two share genetic underpinnings. METHODS:Genome-wide association studies (GWAS) of mood swings and IBS data were used for the study. Genetic correlation was assessed using the linkage disequilibrium score regression (LDSC), genetic covariance analyzer (GNOVA), and SUPERGNOVA method. Two-sample Mendelian randomization (TwoSampleMR) was used to explore the causal relationship between the two conditions. The conditional/conjoint false discovery rate (cond/conjFDR) was used for genetic overlap analysis. Finally, LDSC applied to specific expression gene analysis was performed to identify tissues associated with the two conditions. RESULTS:At the genomic level, mood swings and IBS have global and local genetic correlations. Analysis of the two traits by Mendelian randomization revealed a bidirectional causal relationship. We identified 21 genetic risk loci (concFDR < 0.05) shared by mood swings and IBS, which acted in the same direction on the two traits. Additionally, mood swings and IBS shared 11 sites in the brain tissues as origins. CONCLUSION:The present study suggests the existence of polygenic overlap between mood swings and IBS and provides novel insights into the genetic underpinnings and mechanisms of comorbidities occurring in these two conditions.
BACKGROUND:Glutamate, an excitatory neurotransmitter in the central nervous system, plays a role in neurodevelopment, learning, and memory. It is thought to interact with the GABAergic system in the development of panic symptoms; however, the relationship between blood glutamate levels and panic disorder severity remains unclear. While research on miRNAs is increasing, studies on their role in panic disorder are limited. This study aimed to evaluate blood glutamate levels and the expression of miR-138-2-3p, which affects glutamate receptors, in panic disorder. METHODS:The study included 46 panic disorder patients and 46 healthy controls. All participants completed sociodemographic, Panic Disorder Severity Scale (PDSS), Anxiety Sensitivity Index-3 (ASI-3), and Somatosensory Exaggeration Scale (SSAS) forms. Peripheral venous blood was collected for genetic and biochemical analysis. MicroRNA expression was assessed by real-time PCR, and glutamate levels were measured using ELISA. RESULTS:Patients with panic disorder exhibited significantly lower plasma glutamate levels compared with healthy controls, with median values (25-75% percentiles) of 96.7 nmol/ml (51.39-133.62) versus 209 nmol/ml (95.6-521.9, P < 0.001). Moreover, glutamate levels were negatively associated with symptom severity as measured by the PDSS, ASI-3, and SSAS. In parallel, miR-138-2-3p expression was significantly reduced in patients relative to controls, with median ratios (25-75% percentiles) of 0.27 (0.14-0.57) versus 0.48 (0.23-0.98, P = 0.034), corresponding to a 1.77-fold higher expression in controls. CONCLUSION:Altered miR-138-2-3p expression and reduced peripheral glutamate levels may contribute to the pathophysiology and clinical severity of panic disorder.
