Genetic testing and molecular biomarkers最新文献

Red blood cell (RBC) membranopathies, caused by genetic alterations in membrane and cytoskeletal proteins, lead to significant variability in clinical presentation. This study analyzes 23 single nucleotide variants across nine genes (ADD1, ADD2, ANK1, EPB41, PIEZO1, SLC4A1, SPTA1, SPTB, and TAF3) in 225 Mexican patients with suspected RBC membranopathies and their effects on hematological parameters. Key variants, such as ADD2:c.1797C>T, SPTA1:c.5992G>C, SPTA1:c.6046C>A and SPTA1:c.6531-12C>T, were significantly associated with decreased RBC count, hemoglobin levels, packed cell volume, mean corpuscular hemoglobin and/or mean corpuscular hemoglobin concentration. Additionally, the following six combinations showed significant associations with two or three hematological parameters: SPTA1:c.5992G>C + SPTA1:c.6046C>A, SPTA1:c.5992G>C + ADD1:c.1378G>T, ADD1:c.1378G>T + ADD2:c.1797C>T, ADD1:c.1378G>T + PIEZO1:c.6793A>G, ADD2:c.1797C>T + PIEZO1:c.6793A>G, and TAF3:c.410-2550A>G + SPTA1:c.6531-12C>T. These findings underscore the importance of selected population genetic studies to increase our understanding of genotype-hematological phenotype relationships in RBC membranopathies.

Background: X-linked female-limited high myopia (MYP26, OMIM:301010) is a rare Mendelian subtype of early-onset high myopia (eoHM), with females having progressive myopic refractive error (≥-6 D) and males as asymptomatic carriers. Pathogenic variants in ARR3 (OMIM:301770) have been linked to eoHM, but the spectrum of ARR3 variants in Chinese populations remains incompletely defined.

Objective: To identify the causative variant in a Chinese eoHM family and expand ARR3 variant spectrum for MYP26.

Methods: We conducted clinical and genetic analyses of a Chinese family with eoHM. The proband underwent clinical examinations and whole-exome sequencing (WES). Sanger sequencing validated variants in affected family members, and bioinformatics tools evaluated variant pathogenicity.

Results: WES identified an ARR3 c.214C>T (p.R72X) stop-gain variant, co-segregating with the disease phenotype and predicted to truncate cone arrestin, disrupting phototransduction. A female carrier showing incomplete penetrance (I-1) was identified, which highlights the unrecognized complexity of the pathogenic mechanism underlying MYP26. This variant was first reported in the Chinese population.

Conclusions: Our study expands the ARR3 variant spectrum associated with eoHM, highlighting the role of ARR3 c.214C>T (p.R72X), first reported in Chinese populations. The finding of incomplete penetrance underscores the complexity of X-linked female-limited inheritance and provides a reference for genetic counseling of related families.

Objective: Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort.

Materials and methods: A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models.

Results: The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ² = 22.80, p = 1.1 × 10^-5). The Met (A) allele frequency was significantly higher in patients (43.7% vs. 23.0%; χ² = 15.84, p = 6.9 × 10^-5). Unadjusted analysis showed a protective effect of GG (OR = 0.45, 95% CI: 0.24-0.82) and a markedly increased risk associated with AA (OR = 49.81, 95% CI: 2.95-839.90). Dominant carriers (GA + AA) had increased odds of MDD (OR = 2.23), and each A allele conferred a higher risk (OR = 2.60). These associations remained significant after adjustment for age and sex.

Conclusion: The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression.

Background: Although several approaches have identified individual genes that contribute to autism spectrum disorder (ASD), more research is needed to establish whether these single nucleotide polymorphisms are associated with a lower risk. Studies have found that the oxytocin receptor (OXTR) and arginine-vasopressin receptors (AVPR) genes have an essential role as neuromodulators or neurotransmitters in ASD. Most of these studies have been primarily carried out in the United States, Western Europe, and Australasia, and there is divergence in the conclusions.

Objective: To date, there are no existing studies in Mexico on the possible usefulness of these genes as biomarkers; hence, this study analyzes the association of the rs2254298 in the OXTR1, rs7294536 in the AVPR1a, and rs28632197 in the AVPR1b with ASD.

Methods: Seventy-five samples of children with ASD and 71 samples corresponding to children with neurotypical development were analyzed.

Results: The study found a robust protective association for A allele of the rs28632197 in the AVPR1b, while no effect was found for the rs2254298 and rs7294536.

Conclusion: The importance of these findings is that the protective association can prevent the disorder from occurring or prevent a more severe manifestation. These findings open new avenues for research in the role played by gene-environment interaction in different geographical and ethnic populations.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a respiratory disorder responsible for the global pandemic and widespread mortality. Circular RNAs (circRNAs), one of the newest forms of noncoding RNAs (ncRNAs), are important regulators of the host immune response and viral replication through sponging of microRNAs (miRNAs). This work aims to look at the expression and functions of hsa_circ_0009910/hsa-miR-145-5p/IFN beta 1 (IFNB1) in SARS-CoV-2-related infection and the molecular mechanisms that underpin them. In the experimental phase of the study, total RNA was isolated from the peripheral blood mononuclear cells (PBMCs) of 48 patients with symptomatic COVID-19, 48 patients with nonsymptomatic COVID-19, and 48 negative controls, and then cDNA was synthesized. Next, the expression of these genes was examined with quantitative real-time PCR (qRT-PCR). A receiver operating characteristic (ROC) curve was created to assess each gene's potential as a biomarker. The interactions of hsa_circ_0009910, hsa-miR-145-5p, and IFNB1, also the functional and pathway enrichment analyses, were detected by bioinformatics analysis. When compared with the negative control group, the expression of hsa_circ_0009910 in both symptomatic and nonsymptomatic groups, and IFNB1 in the symptomatic group was higher in the COVID-19 patients. Furthermore, the relative expression of hsa-miR-145-5p in the symptomatic and nonsymptomatic groups was lower than that in the negative control group. In addition, there was a positive correlation between hsa_circ_0009910 and IFNB1 expression, as well as a negative correlation between hsa-miR-145-5p, hsa_circ_0009910, and IFNB1 expressions. hsa-miR-145-5p has a higher area under the curve and may be a more effective biomarker to distinguish COVID-19 patients from the healthy controls, based on ROC curve study, but further study is needed. In conclusion, our data show that the hsa_circ_0009910/hsa-miR-145-5p/IFNB1 triple network may play a role in the pathogenesis of COVID-19 and can be considered a therapeutic target in COVID-19 patients.

Background: Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis and Graves' disease, are characterized by aberrant immune responses influenced by both genetic predisposition and environmental triggers. Genetic association studies have identified several candidate loci that may contribute to the onset and progression of these conditions. The present study investigates the potential impact of specific genetic polymorphisms in interleukin genes (IL17A, IL1B, IL18) and CTLA-4 on thyroid peroxidase antibody (TPOAb) levels in individuals from northwest Iran. Results: A total of 82 individuals with elevated TPOAb levels and 82 antibody-negative controls were genotyped for single nucleotide polymorphisms using the tetra-primer amplification refractory mutation system polymerase chain reaction. The analysis revealed significant associations between specific genetic variants and TPOAb levels. Notably, the AG genotype of IL17A rs4711998 was associated with a protective effect, whereas the AA genotype of IL1B rs16944 was correlated with elevated antibody levels, suggesting a potential role in enhancing autoimmune responses. Conclusions: These findings underscore the contribution of genetic variations in interleukin genes to the pathogenesis of AITDs in the northwest Iranian population. Elucidating these associations may enhance our understanding of disease mechanisms and contribute to the development of targeted therapeutic strategies.

Background: Familial exudative vitreoretinopathy (FEVR) is a rare inherited ocular disorder characterized by abnormal peripheral retinal vascular development. KIF11 variants are known to cause autosomal dominant FEVR, but novel pathogenic variants remain to be identified. Objective: This study aimed to identify a novel causative variant of FEVR and provide evidence for genetic counseling. Methods: Whole-exome sequencing was performed on members of a Chinese family with FEVR. Rare variants with a gnomAD allele frequency <0.1% in East Asian and general populations were prioritized. Sanger sequencing was used for validation, and bioinformatic analyses (including Combined Annotation Dependent Depletion [CADD] score and cross-species conservation analysis) were conducted to assess pathogenicity. Results: A novel heterozygous frameshift variant KIF11 c.1239_1240del (p.V414Sfs*9) was identified in the proband, his brother, and his mother. This variant, absent from public databases (1000 Genomes, ExAC, gnomAD), had a CADD score of 26.9 and affected a highly conserved residue, suggesting disruptive effects on protein structure. The proband's mother showed macular involvement. Conclusions: The novel KIF11 frameshift variant (c.1239_1240del p.V414Sfs*9) identified in a Chinese family expands the mutation spectrum of autosomal dominant FEVR, with macular involvement aiding clinical prognostic assessment.

Background: Methyltransferase proteins, including SET Domain Containing 7 (SETD7), play an important role in the initiation of carcinogenesis through epigenetic mechanisms. Due to the reduced chance of survival in colorectal cancer (CRC), it is necessary to find molecular methods to detect CRC in the early stages. This study aimed to investigate the expression of SETD7 in metastatic and nonmetastatic tumor tissues in CRC compared with healthy tissue in order to evaluate its potential as a biomarker for the diagnosis of CRC in the early stages. Methods: In this study, the expression level of the SETD7 gene in primary colon adenocarcinoma was analyzed using the UALCAN database. To confirm the bioinformatics data, SETD7 gene expression was investigated in 80 colorectal tumor tissues (metastatic and nonmetastatic) and adjacent normal tissues using RT-qPCR. Results: According to the results obtained from the UALCAN database, SETD7 expression is significantly increased in tumor tissues compared with normal tissues, which was confirmed by the RT-qPCR results. We showed that although the SETD7 expression level in colorectal tumor tissues was higher than in adjacent normal tissues (p = 0.0001), this increase was only statistically significant in nonmetastatic tumor tissues (p = 0.0001). Based on receiver operating characteristic (ROC) analysis, increased SETD7 gene expression can be used as a good biomarker to distinguish tumor tissue from normal tissue in the early stages (area under the ROC curve = 0.85). Conclusion: Increased SETD7 gene expression can be used as an epigenetic marker in tissue-based prognosis and screening of CRC in the early tumor stages.

Noncoding RNAs (ncRNAs) comprise a significant portion of the transcriptome and contribute to various cellular and molecular processes and disease development. Although many functional roles for ncRNAs have been discovered, the regulatory functions of many require further elucidation. Intervertebral disk degeneration (IDD) is a leading cause of lower back pain and represents a major social and financial challenge worldwide. This review summarizes the literature on long ncRNAs and circular RNAs as novel regulators in IDD development. IDD diminishes quality of life, underscoring the importance of research on its pathogenesis and the identification of novel therapeutic targets. The definitive cellular and molecular mechanisms underlying IDD pathogenesis remain unidentified, and no effective treatment is available. Both genetic and environmental or lifestyle factors are associated with IDD development. Therefore, understanding the exact molecular mechanisms of IDD could yield novel therapeutic targets.

Background: Postaxial polydactyly (PAP) is characterized by the development of extra digits at the fifth finger. It can occur as an isolated disease or a part of a syndrome. The genetic basis of nonsyndromic PAP has been linked to sequence variants in different genes. The aim of the present study was to identify the causative genetic variants in four Pakistani families demonstrating PAP. Methods: Causative genetic variants were identified using whole-exome sequencing and microsatellite mapping, followed by validation through Sanger sequencing. Further analysis was carried out through conservation, structural modeling, and 100-ns molecular dynamic simulations of GLI1. Results: Whole-exome and targeted sequencing in four families (A, B, C, and D) identified novel variants in the GLI1 (c.1013G>T; p.Cys338Phe), and GLI3 (c.2003C>T; p.Pro668Leu and c.4564delG; p.Ala1522ProfsTer2), and a recurrent variant in IQCE genes (c.895_904del; p.Val301SerfsTer8) linked to 7p22.3. All the variants were highly conserved across different species. Comparative analysis of the GLI1^WT and GLI1^Cys338Phe proteins revealed domain fluctuations leading to the loss of structurally and functionally important inter- and intramolecular interactions. The three-dimensional structural analysis of the GLI3 protein showed that the missense variant p. (Pro668Leu) disturbed the protein folding and intra-residue interaction, while the frameshift variant p. (Ala1522ProfsTer2) led to the loss of the C-terminus of the protein. Similarly, the IQCE structural analysis confirmed the loss of protein function due to frameshift and C-terminal deletion. Conclusion: This study has broadened the phenotypic and allelic spectrum of the genes associated with isolated PAP and strengthened the role of these genes in regulating limb development.