Frontiers in Genetics最新文献

The Tylorrhynchus heterochaetus, a polychaete benthic invertebrate belonging to the Nereididae family, has emerged as a promising aquaculture species. It is highly regarded for its nutritional profile, with protein accounting for up to 60% of its dry weight, as well as its balanced amino acid composition. This has earned it the nickname "aquatic cordyceps". However, wild populations of this species have declined significantly due to environmental shifts and human activities, with local extinctions reported in certain regions. A critical barrier to advancing its population genetics and conservation biology has been the absence of a chromosomal-level reference genome for T. heterochaetus. To address this gap, we present the first chromosome-level genome assembly of T. heterochaetus, generated using PacBio HiFi sequencing data and Hi-C technology. The final assembly spans 782.25 Mb with a scaffold N50 of 75.39 Mb, successfully anchored to 11 pseudo-chromosomes. Repetitive sequences account for 428.09 Mb (54.73%) of the genome, and 20,145 protein-coding genes were annotated. This study provides foundational insights into the genetics, genomics, and evolutionary history of T. heterochaetus, laying a critical groundwork for future research and enabling the development of targeted genetic conservation strategies.

Background: Parkinson's disease (PD) is influenced by various factors, with lysosome function playing a critical role. However, the specific involvement of lysosome-related genes (LRGs) in PD remains unclear.

Objective: This study aims to identify biomarkers specific to PD that exhibit robust disease prediction capabilities.

Methods: Datasets for patients with PD, LRGs, and inflammation-related genes (IRGs) were retrieved from online databases. miRNAs and mRNAs within key modules were selected through Weighted Gene Co-expression Network Analysis (WGCNA), revealing strong associations with PD. A miRNA-mRNA network was constructed based on highly correlated PD-related LRGs (PD-LRGs) and miRNAs within these modules. Candidate genes were identified by intersecting target genes, differentially expressed genes (DEGs), PD-LRGs, and module-associated mRNAs. Machine learning and expression validation were employed to confirm these biomarkers. A nomogram was established, and its diagnostic performance was evaluated using a confusion matrix. Drug predictions were conducted based on these biomarkers. Spearman's correlation analyses were performed to assess the relationship between IRGs, freezing of gait (FOG)-related genes, and biomarkers. Molecular regulatory networks were constructed using datasets and online resources. Finally, clinical samples were collected for quantitative PCR (qPCR) validation of biomarker expression.

Results: Key modules related to PD were identified, comprising 190 miRNAs and 7,633 mRNAs. A miRNA-mRNA network was constructed based on 55 PD-LRGs and 181 miRNAs, resulting in the identification of 26 candidate genes strongly linked to lysosomal function. FGD4 and MAN2B1 were selected as biomarkers, and a gene expression-based risk prediction table was created. These biomarkers were significantly correlated with IRGs and several FOG-related genes. Gene localization analysis revealed that FGD4 and LRRK2, both critical to the FOG pathway, are located on chromosome 12. Drug prediction revealed that Tetrachlorodibenzodioxin and bisphenol A target both FGD4 and MAN2B1. qPCR analysis confirmed that FGD4 and MAN2B1 expression levels were significantly higher in patients with PD compared to healthy controls (p < 0.05).

Conclusion: FGD4 and MAN2B1 act as lysosomal biomarkers associated with PD and exhibit strong correlations with genes involved in PD-related freezing of gait. This study offers novel insights into PD diagnosis.

Geleophysic dysplasia represents an exceedingly uncommon autosomal recessive skeletal disorder marked by profound growth restriction, contractures affecting multiple joints, and cardiac valve abnormalities. The molecular foundation involves ADAMTSL2 gene mutations disrupting extracellular matrix architecture. We document a 29-year-old Taiwanese woman followed longitudinally for 25 years, presenting with severe short stature measuring 141.2 cm, widespread joint contractures, thoracolumbar scoliosis, and distinctive gait abnormalities. Whole-exome sequencing identified compound heterozygous ADAMTSL2 mutations: c.286C>T resulting in p. Arg96Trp and c.454_459del causing p. Cys152_Thr153del deletion. The clinical course revealed musculoskeletal deterioration alongside mild mitral valve involvement and os odontoideum. Bilateral glaucoma, consistent with previously reported ocular manifestations in geleophysic dysplasia, was diagnosed at age 26. Notably, recent ophthalmologic evaluation revealed keratoconus-like corneal ectasia with paradoxically increased central corneal thickness measuring 690-693 μm bilaterally, substantially exceeding normal values of 520-560 μm. This paradoxical corneal thickening, contrasting with the stromal thinning characteristic of classical keratoconus, represents a novel ADAMTSL2-related corneal phenotype. The patient maintained normal intellectual capacity despite physical limitations, contrasting with published early mortality rates approaching 33%. This extended clinical documentation establishes keratoconus-like corneal ectasia with paradoxical corneal thickening as a novel ophthalmologic manifestation in geleophysic dysplasia, while adding to prior reports of glaucoma in this condition. These findings emphasize the necessity for comprehensive ophthalmologic monitoring in ADAMTSL2-related disorders and supporting multidisciplinary management strategies.

The FK506 Binding Protein 5 (FKBP5) gene encodes a protein that binds to the immunosuppressive agent FK506. FKBP5 expression is regulated by genetic variation and epigenetic mechanisms, including DNA methylation (DNAm). This gene regulates the glucocorticoid receptor (GR), and aberrant FKBP5 methylation is associated with psychiatric and metabolic disorders. Recent evidence also indicates that FKBP5 methylation significantly influences malignant tumors. The methylation status of FKBP5 not only modulates its own expression but also contributes to disease pathogenesis by regulating downstream signaling pathways. Despite extensive research on FKBP5 in individual disease contexts, a critical gap remains in understanding how its DNAm serves as a unifying epigenetic mechanism across psychiatric, metabolic, and neoplastic disorders. Existing reviews often focus on single disease domains or on genetic and protein-level regulation, lacking a systematic, horizontal integration analysis centered on DNAm-a dynamic and reversible modification. This review aims to fill this gap by proposing a coherent "epigenetic regulatory framework" that elucidates how tissue-and site-specific FKBP5 DNAm patterns, through modulating glucocorticoid (GC) signaling, stress responses, and inflammatory pathways (e.g., NF-κB), contribute to divergent pathological outcomes. By integrating evidence from disparate fields, this review summarizes the role of FKBP5 DNAm in disease biology, its functions across various disorders, and its potential as a biomarker and therapeutic target, aiming to provide a theoretical foundation and strategic insights for disease diagnosis and treatment.

Individuals with rare genetic diseases collectively comprise 3.5%-5.9% of the population, roughly 400 million people worldwide. Undiagnosed rare disease programs have leveraged next-generation sequencing technologies to facilitate genetic diagnoses, thereby shortening the complex diagnostic odysseys that many of these patients and their families endure. However, enrollment data suggest disparities in access to undiagnosed genetic disease programs among racial and ethnic minorities. To better understand this issue, we conducted a retrospective review of our rare undiagnosed disease program to assess whether referral route was a determinant of disparities for minoritized racial and ethnic communities. Participants enrolled in the Yale Pediatric Genomics Discovery Program from 2016 to 2022 were self-categorized into four racial and ethnic groups: Hispanic/Latinx (any race), non-Hispanic White, non-Hispanic Black/African American, non-Hispanic Other. Route of referral was classified as Inpatient, Outpatient, or Outside/Self referrals. Completion rates were the percentage of participants who completed enrollment compared to their respective group. Demographics for program participants were different from Yale-New Haven Children's Hospital demographics, with over-representation of non-Hispanics Whites. Direct inpatient recruitment had a higher yield of Hispanic individuals, which was offset by under-representation of minoritized individuals in the Outside/Self setting. Inpatients had lower referral completion rates compared to Outpatient and Outside/Self referrals. These data suggest that the route of referral may represent different levels of access to care, and inpatient recruitment may be leveraged to promote participation by some minoritized communities. We encourage other programs to examine their cohorts for representation and identify strategies for improving participation.

Elective Genomic Testing (EGT) can identify individuals at risk for actionable conditions that would not come to clinical attention following current testing guidelines. We describe the results of a checkup unit from a leading Spanish University hospital (Clínica Universidad de Navarra, Spain) that has incorporated EGT to their regular clinical practice. Medical anamnesis, biochemistry, low-intensity whole body scan and EGT with interpretation of over 560 genes related to actionable adult-onset diseases (Veritas Intercontinental, Spain) was performed in 400 participants, including medical consultation before and after the checkup. Clinically relevant variants were identified in 79/400 participants (19.8%). Thirteen individuals (3.3%) presented with clinical variants included in the American College of Medical Genetics and Genomics secondary finding list (ACMG SF list); 69.2% of these variants showed potential association with personal or family history (PFH). The study presents the results of the first hospital integrating EGT into the checkup unit.

Objective: This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children.

Methods: Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted.

Results: The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain (SPTB)gene (NM_001355436.2) and a missense mutation, c.292G>A (p.Ala98Thr), in the lipoprotein lipase (LPL) gene (NM_000237.3). The SPTB c.6005G>A (p.Trp2002*) mutation was inherited from the mother, who exhibited mild anemia, jaundice, and splenomegaly. The LPL c.292G>A (p.Ala98Thr) mutation was inherited from the father, who had hypertriglyceridemia. The SPTB c.6005G>A (p.Trp2002*) mutation is extremely rare in the general population.

Conclusion: The heterozygous mutations SPTB c.6005G>A (p.Trp2002*) and LPL c.292G>A (p.Ala98Thr) are the pathogenic causes in this family and provide a basis for clinical management and genetic counseling. Based on the HGMD, 1000G, and ExAC databases, the SPTB c.6005G>A (p.Trp2002*) mutation is reported here for the first time, enriching the mutation spectrum of the SPTB gene.

Background: Intervertebral disc degeneration (IDD) is a major contributor to low back pain, yet its molecular mechanisms remain unclear. Identifying potential druggable genes (PDGs) associated with IDD could facilitate early diagnosis and targeted therapy. This study aimed to explore the diagnostic and mechanistic significance of PDGs in IDD.

Methods and results: Three GEO datasets were merged as a training set, with another blood-based dataset as testing. PDGs were obtained from the literature and intersected with differentially expressed genes (DEGs). Functional enrichment and immune infiltration analyses were performed. A Lasso regression model was developed for diagnosis, and Mendelian Randomization (MR) analysis inferred causality. Cellular experiments validated key gene expression. Fourteen differentially expressed PDGs were identified, primarily involved in immune responses and neutrophil activity. A five-gene diagnostic model (BPI, CD160, CTSG, CYP27A1, KIF11) was constructed and demonstrated high accuracy. MR analysis confirmed a causal relationship between BPI and CTSG with IDD. GSEA revealed that BPI was negatively associated with oxidative phosphorylation, while CTSG was linked to the G2M checkpoint. Cellular experiments confirmed BPI and CTSG upregulation in TNF-α-induced NPCs.

Conclusion: This study constructed a diagnostic model and identified BPI and CTSG as potential biomarkers for IDD, providing new insights into IDD treatment.

Polycystin-1 (PC1), encoded by the PKD1 gene, forms a complex with polycystin-2 (PKD2; 173910) that regulates multiple signaling pathways to maintain normal renal tubular structure and function. Mutations in the PKD1 gene are the primary cause of type 1 PKD (polycystic kidney disease), accounting for 78%-85% of all PKD cases. In this study, we report a case of a boy presenting with microscopic hematuria with multiple renal cysts and carrying an unreported intronic variant, c.12445-34_12445-10del, in the PKD1 gene inherited from his father who also presented PKD. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for minigene splicing assays showed two abnormal splicing alterations with the c.12445-34_12445-10del variant at the mRNA level: one causes a 16-bp deletion in exon 46, resulting in premature protein termination (p.Phe4149GlyfsTer45), and the other results in a 205-bp deletion, leading to delayed termination (p.Phe4149ProfsTer139). Based on the clinical characteristics and gene mutations with functional verification, the patient was finally diagnosed with PKD caused by PKD1 function defection, as confirmed by the combined clinical features and genetic analysis. Management strategies include dietary management, blood pressure monitoring, and regular follow-up of kidney function. This is the first study to report an intronic deletion in the PKD1 gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PKD1-related diseases and highlight the importance of genetic counseling for the family.