Psychiatric Genetics最新文献

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.

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.

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.

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.

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: 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.

Background: Newborn screening (NBS) is a public health service aimed at identifying infants with severe genetic disorders. Genetic testing is now commonly used for secondary or confirmatory testing after a positive result in some NBS programs. Recently, next-generation sequencing (NGS) has emerged as a robust tool that enables large panels of genes to be scanned together rapidly. Rapid advances in NGS emphasize the potential for genomic sequencing to improve NBS programs. Neonatal genetic screening represents a critical advancement within contemporary NBS frameworks, integrating NGS to enhance disease detection sensitivity and specificity.

Materials and methods: This study, conducted through multicenter collaboration in Changsha, screened 2019 neonatal samples for 75 common genetic disorders involving 135 pathogenic genes. The aim was to explore the incidence and mutation spectrum of these disorders in the Chinese population and to propose an optimized screening model.

Results: The results showed a positive detection rate of 0.74% and a carrier rate of 31.50%.

Conclusion: This study provides valuable data for refining neonatal genetic screening protocols in China.