Gene Variants Research Articles

LRRK2-Associated Parkinsonism With and Without In Vivo Evidence of Alpha-Synuclein Aggregates.

Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient-reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta 1-42 , total tau, phospho-tau 181 , urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups. 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.

Mild Aromatic L-Amino Acid Decarboxylase Deficiency: As A Reason For Hypoketotic Hypoglycemia In A 4-Year-Old Girl.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a disease in which neurological findings are dominant due to deficiencies in neurotransmitter synthesis; hypoglycemia caused by autonomic dysfunction is one of the symptoms that may be encountered. Here we report a mild AADC deficiency presenting with hypoglycemia without a neurological sign. A 4-year-old girl presented with recurrent hypoglycemia. Her growth and development were normal. Plasma insulin and cortisol values were normal in the sample at the time of hypoglycemia. The C8:1-Carnitine elevation was detected in the acylcarnitine profile. The clinic exome panel was performed with the suggestion of a fatty acid oxidation defect. However, a homozygous variant in the DDC gene was detected. On top of that, CSF neurotransmitter analysis revealed low 5-hydroxy indol acetic ( 5 HIAA ) and homovanillic acid ( HVA ) and high 3-O-methyl-dopa and methyltetrahydrofolate ( 5 MTHF ) consistent with AADC deficiency. Plasma AADC enzyme activity was low. The episodes of hypoglycemia were treated with uncooked cornstarch. Our case emphasizes that AADC deficiency should be considered in patients with hypoglycemia.

A de novo PRPF8 Pathogenic Variant in Transient Severe Hypophosphatemia with Delayed Puberty and Growth Failure.

Childhood hypophosphatemia is a rare condition and may be caused by malabsorption, malignancies, or genetic factors. Prolonged hypophosphatemia leads to impaired growth and radiographic signs of rickets. We performed a detailed clinical and genetic evaluation of an adolescent boy with repeatedly low plasma phosphate concentrations (below 0.60 mmol/L) and growth failure. At 14 years, the patient presented with decelerating growth and delayed puberty. Biochemistry showed hypophosphatemia due to increased urinary phosphate loss; kidney function and vitamin D status were normal. Radiographs showed mild metaphyseal changes. A gene panel for known genetic hypophosphatemia was negative. Trio exome analysis followed by Sanger sequencing identified a pathogenic heterozygous de novo stop-gain variant in PRPF8 gene, c.5548C&gt;T p.(Arg1850*), in the conserved RNase H homology domain. PRPF8 encodes the pre-RNA protein 8, which has a role in RNA processing. Heterozygous PRPF8 variants have been associated with retinitis pigmentosa and neurodevelopmental disorders but not with phosphate metabolism. The patient underwent growth hormone (GH) stimulation tests which confirmed GH deficiency. Head MRI indicated partially empty sella. GH treatment was started at 15 years. Surprisingly, phosphate metabolism normalized during GH treatment, suggesting that hypophosphatemia was at least partly secondary to GH deficiency. The evaluation of an adolescent with profound long-term hypophosphatemia revealed a pituitary developmental defect associated with a stop-gain variant in PRPF8. Hypophosphatemia alleviated with GH treatment. The pathological PRPF8 variant may contribute to abnormal pituitary development; however, its role in phosphate metabolism remains uncertain.

Clinical and molecular characteristics of Kabuki syndrome patients with missense variants-novel features and literature review.

Kabuki Syndrome (KS) encompasses a spectrum of clinical manifestations, primarily attributed to pathogenic variants in the KMT2D gene. This study aims to elucidate novel features in KS patients with missense variants, contrasting their presentation with both literature-reported cases of patients with missense pathogenic variants as well as other KS patients with truncating pathogenic variants. Employing a survey questionnaire and clinical evaluations, we examined ten KS patients with missense variants, focusing on their dysmorphism characteristics, behavior and psychomotor development. We identified unique features in missense variant patients, including foot hyperesthesia, musicality, and sensory integration disorders. Notably, despite similarities in developmental trajectories, distinct phenotypic traits emerged in missense variant cases, suggesting a potential genotype-phenotype correlation. These findings contribute to a deeper understanding of KS heterogeneity and underscore the importance of genotype-specific characterization for prognostic and therapeutic considerations. Further exploration of genotype-phenotype relationships promises to refine clinical management strategies and enhance patient outcomes in this complex syndrome.

Pan-cancer analyses reveal the molecular and clinical characteristics of TET family members and suggests that TET3 maybe a potential therapeutic target.

The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer.

Association between CYP1A2 gene variants −163 C/A (rs762551) and −3860 G/A (rs2069514) and bladder cancer susceptibility

BackgroundBladder cancer (BLCA) poses a significant global health challenge due to its high incidence, poor prognosis, and limited treatment options.Aims and objectivesThis study aims to investigate the association between two specific polymorphisms, CYP1A2-163 C/A and CYP1A2-3860G/A, within the Cytochrome P450 1A2 (CYP1A2) gene and susceptibility to BLCA.MethodsThe study employed a case-control design, genotyping 340 individuals using Polymerase Chain Reaction-High-Resolution Melting Curve (PCR-HRM). Various genetic models were applied to evaluate allele and genotype frequencies. Genetic linkage analysis was facilitated using R packages.ResultsThe study reveals a significant association with the − 163 C/A allele, particularly in the additive model. Odds ratio (OR) analysis links CYP1A2-163 C/A (rs762551) and CYP1A2-3860G/A(rs2069514) polymorphisms to BLCA susceptibility. The rs762551 C/A genotype is prevalent in 55% of BLCA cases and exhibits an OR of 2.21. The A/A genotype has an OR of 1.54. Regarding CYP1A2-3860G/A, the G/A genotype has an OR of 1.54, and the A/A genotype has an OR of 2.08. Haplotype analysis shows a predominant C-C haplotype at 38.2%, followed by a C-A haplotype at 54.7%, and a less frequent A-A haplotype at 7.1%. This study underscores associations between CYP1A2 gene variants, particularly rs762551 (CYP1A2-163 C/A), and an increased susceptibility to BLCA. Haplotype analysis of 340 individuals reveals a predominant C-C haplotype at 38.2%, followed by a C-A haplotype at 54.7%, and a less frequent A-A haplotype at 7.1%.ConclusionIn conclusion, the − 163 C/A allele, C/A genotype of rs762551, and G/A genotype of rs2069514 emerge as potential genetic markers associated with elevated BLCA risk.

Rare Variants of the SMN1 Gene Detected during Neonatal Screening.

During the expanded neonatal screening program conducted in 2023, we analyzed samples obtained from 1,227,130 out of 1,256,187 newborns in the Russian Federation in order to detect 5q spinal muscular atrophy (5q SMA). Within the 253-sample risk group formed based on the results of the first screening stage, 5 samples showed a discrepancy between the examination results obtained via various screening methods and quantitative MLPA (used as reference). The discrepancy between the results was caused by the presence of either a c.835-18C>T intronic variant or a c.842G>C p.(Arg281Thr) missense variant in the SMN1 gene, both of which are located in the region complementary to the sequences of annealing probes for ligation and real-time PCR. Three newborns had the c.835-18C>T variant in a compound heterozygous state with a deletion of exons 7-8 of the SMN1 gene, one newborn with two copies of the SMN1 gene had the same variant in a heterozygous state, and one newborn had both variants-c.835-18C>T and c.842G>C p.(Arg281Thr)-in a compound heterozygous state. Additional examination was carried out for these variants, involving segregation analysis in families, carriage analysis in population cohorts, and RNA analysis. Based on the obtained results, according to the ACMG criteria, the c.835-18C>T intronic variant should be classified as likely benign, and the c.842G>C p.(Arg281Thr) missense substitution as a variant of uncertain clinical significance. All five probands are under dynamic monitoring. No 5q SMA symptoms were detected in these newborns neonatally or during a 1-year follow-up period.

Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy.

Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale. In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23-197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (-22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.

Expanding the phenotype of NEDAMSS with a psychiatric perspective: analysis of a new case, and a systematic review of the literature.

Pathogenic variants in the IRF2BPL gene are associated with neurodevelopmental disorders with varying degrees of regression, loss of speech and epilepsy. The phenotype is also known as Neurodevelopmental Disorder with regression, Abnormal Movements, loss of Speech, and Seizures (NEDAMSS). The motor symptoms of this disorder share significant phenotypical characteristics with catatonia, a severe neuropsychiatric psychomotor syndrome. The objective of this article isto expand the knowledge on the presentation of NEDAMSS with afocus on psychiatric symptoms including catatonia. A systematic review of 32 case presentations of NEDAMSS, and a novel case report of a patient with NEDAMSS, exhibiting multiple psychiatric symptoms, including catatoniaare presented. Psychiatric symptoms and disorders including affective disorders, psychotic symptoms, catatonia, and developmental disorders are reported in one third of the reviewed cases. Reported effects of pharmacological treatment on motor symptoms of NEDAMSS are very limited. Our case presents improvement in motor symptoms originally attributed to NEDAMSS, after treatment with Lorazepam following diagnosis with catatonia. Patients with NEDAMSS may present with both neurological and psychiatric symptoms. The clinical presentation of NEDAMSS motor symptoms and catatonia have similarities and thus poses significant challenges to the diagnostic process, with risk of incorrect or delayed treatment. The limited experience and the complex phenotype of NEDAMSS complicates pharmacological treatment and encourages caution, especially with the use of antipsychotic drugs in the presence of possible catatonic symptoms.

Detection of hemophilia A genetic variants using third-generation long-read sequencing

BackgroundHemophilia A (HA) is an X-linked recessive genetic disorder caused by pathogenic variations of the factor VIII −encoding gene, F8 gene. Due to the large size and diverse types of variations in the F8 gene, causative mutations in F8 cannot be simultaneously detected in one step by traditional molecular analysis, and genetic molecular diagnosis and prenatal screening of HA still face significant difficulties and challenges in clinical practice. Therefore, we aimed to develop and validate an efficient, accurate, and time-saving method for the genetic detection of HA. MethodsA comprehensive analysis of hemophilia A (CAHEA) method based on long-range PCR and long-read sequencing (LRS) was used to detect F8 gene mutations in 14 clinical HA samples. The LRS results were compared with those of the conventional methods to evaluate the accuracy and sensitivity of the proposed approach. ResultsThe CAHEA method successfully identified 14 F8 variants in all probands, including 3 small insertion deletions, 4 single nucleotide variants, and 7 intron 22 inversions in a “one-step” manner, of which 2 small deletions have not been reported previously. Moreover, this method provided an opportunity to analyze the mechanism of rearrangement and the pathogenicity of F8 variants. The LRS results were validated and found to be in 100% agreement with those obtained using the conventional method. ConclusionOur proposed LRS-based F8 gene detection method is an accurate and reproducible genetic screening and diagnostic method with significant clinical value. It provides efficient, comprehensive, and accurate genetic screening and diagnostic services for individuals at high risk of HA as well as for premarital and prenatal populations.

Common polygenic variation in the early medication change (EMC) cohort affects disorder risk, but not the antidepressant treatment response

BackgroundGiven the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort. MethodsIn this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined. ResultsPGS for MDD was significantly associated with disorder status (NkR2 = 2.48 %, p < 1*10−12), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR. LimitationsThe study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS). ConclusionsThe present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes.

A panel sequencing dataset of peripheral blood gene variations in pan-cancer

Circulating cell-free DNA (cfDNA) in the peripheral blood is a promising biomarker for cancer diagnosis and prognosis. Somatic mutations identified in cancers have been used to detect therapeutic targets for clinical transformation and individualize drug selection, while germline variants can predict a patient’s risk of developing cancer and drug sensitivity. However, no platform has been developed to analyze, calculate, integrate, and friendly visualize these pan-cancer cfDNA mutations deeply. In this work, we performed panel sequencing encompassing 1,115 cancer-related genes across 16,659 cancer patients, spanning 27 cancer types. We detected 496 germline variants in leukocytes and 11,232 somatic mutations in the cfDNA of all patients. CPGV (Cancer Peripheral blood Gene Variations), a database constructed from this dataset, is the first pan-cancer cfDNA database that encompasses somatic mutations, germline variants, and further comparative analyses of mutations across different cancer types. It bears great promise to serve as a valuable resource for cancer research.

Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.

Dysfunction of some mitochondrial aminoacyl-tRNA synthetases (encoded by the KARS1, HARS2, LARS2 and NARS2 genes) results in a great variety of phenotypes ranging from non-syndromic hearing impairment (NSHI) to very complex syndromes, with a predominance of neurological signs. The diversity of roles that are played by these moonlighting enzymes and the fact that most pathogenic variants are missense and affect different domains of these proteins in diverse compound heterozygous combinations make it difficult to establish genotype-phenotype correlations. We used a targeted gene-sequencing panel to investigate the presence of pathogenic variants in those four genes in cohorts of 175 Spanish and 18 Colombian familial cases with non-DFNB1 autosomal recessive NSHI. Disease-associated variants were found in five cases. Five mutations were novel as follows: c.766C>T in KARS1, c.475C>T, c.728A>C and c.1012G>A in HARS2, and c.795A>G in LARS2. We provide audiograms from patients at different ages to document the evolution of the hearing loss, which is mostly prelingual and progresses from moderate/severe to profound, the middle frequencies being more severely affected. No additional clinical sign was observed in any affected subject. Our results confirm the involvement of KARS1 in DFNB89 NSHI, for which until now there was limited evidence.

Associations of CYLD, JAK2 and TLR4 Genotypes with PSA Levels and Immunophenotype in Benign Prostatic Hyperplasia and Prostate Cancer.

Prostate cancer (PCa) is one of the most common malignant tumors of the male urinary system, and its incidence and mortality rates have been increasing worldwide. Benign prostatic hyperplasia (BPH) represents stromal and epithelial cell proliferation in the prostate in elderly males. Abnormal activation of inflammation-related signalling molecules, such as toll-like receptor 4 (TLR4) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) has been linked to the initiation and progression of various human diseases including PCa and BPH. Cylindromatosis (CYLD) gene alterations are associated with PCa progression. In this study, the contribution of CYLD, JAK2, and TLR4 gene variants to PCa and BPH risks and their associations with prostate-specific antigen (PSA) levels, immunophenotype, and clinical features in Vietnamese men were determined. A total of 102 patients with PCa, 65 with BPH, and 114 healthy controls were enrolled. The immunophenotype was analyzed by flow cytometry, cytokine secretion by enzyme-linked immunosorbent assay (ELISA), and gene variants by DNA sequencing. Lower levels of transforming growth factor β (TGF-β) and higher numbers of CD13+CD117- and CD56+CD25+ cells were observed in the PCa group than in the BPH group. Genetic analysis of the CYLD gene identified five single nucleotide polymorphisms (SNPs), of which c.2351-47 C>T, c.2351-46A>T, and rs1971432171 T>G had significantly higher frequencies in PCa patients than in the control and BPH groups. Sequencing of the TLR4 gene revealed five nucleotide changes, in which the rs2149356 SNP showed an increased risk for both PCa and BPH and the c.331-206 SNP had a reduced risk for PCa. Importantly, the expansion of activated natural killer (NK) cells and higher levels of PSA were found in PCa patients carrying the CT genotype of the CYLD c.2351-47 compared to those with the wild-type genotype. Activation of NK cells in CYLD-sensitive PCa patients was associated with serum PSA release and the CYLD c.2351-47 variant may be a significant risk factor for prostatitis in PCa patients.

Intermediate uveitis in common variable immunodeficiency (CVID) associated with a heterozygous variant in the TNFRSF13B gene.

To report on a rare case of intermediate uveitis occurring in a patient with common variable immunodeficiency (CVID) and a heterozygous TNFRSF13B variant. Observational case report. A 23-year-old male presented with a 3-month history of increasing floaters and blurred vision to both eyes. He had been treated with topical and intravitreal corticosteroids by his local ophthalmologist nine months before. Ocular examination demonstrated bilateral intermediate uveitis with retinal vasculitis. He had been treated with intravenous immunoglobulins during childhood, due to primary humoral immunodeficiency. Systemic work-up for other causes of intermediate uveitis was unremarkable, notably no features of systemic sarcoid-like disease were detected. Initial treatment with mycophenolate mofetil showed insufficient response, and upon switching to adalimumab, clinical remission was achieved. Immunocytometry and genetic work-up revealed a smB+CD21norm subtype of CVID and a heterozygous TNFRSF13B variant. This report of CVID-associated intermediate uveitis in a patient with a heterozygous TNFRSF13B variant highlights the potential involvement of the eye within CVID-associated autoimmunity and the role for anti-TNF blockade in this challenging group of patients.

Beyond the 10%: Unraveling the genetic diversity in Turkish cystic fibrosis patients not eligible for CFTR modulators.

Cystic fibrosis (CF) is an autosomal recessive disease caused by variants of CFTR gene. Over 2000 variants have been identified, and new drugs called CFTR modulators have been developed to target specific defects in the CFTR protein. However, these drugs are only suitable for patients with certain variants of CFTR, and eligibility rates vary depending on race and geographical region. This study aimed to reveal the detailed genotype and clinical characteristics of people with CF (pwCF) at our center in Turkey, a developing country, who are not eligible for CFTR modulators. A total of 445 pwCF followed up at Marmara University were reviewed retrospectively. Variants of the patients ineligible to CFTR modulators were classified based on American College of Medical Genetics guidelines, CFTR classification, the change in the encoded protein, and the variant type. The study revealed that 139 (31.2%) patients weren't eligible for CFTR modulators. There were 60 different variants in the 276 alleles, as two were missing. The majority of patients had missense or nonsense variants, and that the most common variant was c.1545_1546del, which can be said unique to this geography. The study highlights the importance of detecting the variants of ineligible patients in detail to guide future approaches for more targeted and effective interventions in CF care. Testing the effectiveness of CFTR modulators for rare or newly occurring variants is crucial to ensure equal access for pwCF to these therapies from different racial backgrounds and ethnic minorities.

Allelic variations in the chpG effector gene within Clavibacter michiganensis populations determine pathogen host range.

Plant pathogenic bacteria often have a narrow host range, which can vary among different isolates within a population. Here, we investigated the host range of the tomato pathogen Clavibacter michiganensis (Cm). We determined the genome sequences of 40 tomato Cm isolates and screened them for pathogenicity on tomato and eggplant. Our screen revealed that out of the tested isolates, five were unable to cause disease on any of the hosts, 33 were exclusively pathogenic on tomato, and two were capable of infecting both tomato and eggplant. Through comparative genomic analyses, we identified that the five non-pathogenic isolates lacked the chp/tomA pathogenicity island, which has previously been associated with virulence in tomato. In addition, we found that the two eggplant-pathogenic isolates encode a unique allelic variant of the putative serine hydrolase chpG (chpGC), an effector that is recognized in eggplant. Introduction of chpGC into a chpG inactivation mutant in the eggplant-non-pathogenic strain Cm101, failed to complement the mutant, which retained its ability to cause disease in eggplant and failed to elicit hypersensitive response (HR). Conversely, introduction of the chpG variant from Cm101 into an eggplant pathogenic Cm isolate (C48), eliminated its pathogenicity on eggplant, and enabled C48 to elicit HR. Our study demonstrates that allelic variation in the chpG effector gene is a key determinant of host range plasticity within Cm populations.

Genetic variation of FUT3 gene in the Han population from Northern China.

The FUT3 gene encodes α(1,3/1,4)-fucosyltransferase, which is a crucial enzyme in the synthesis of Lewis antigens. FUT3 gene variants show race-specific differences. In this study, we conducted a systematic sequence analysis of the FUT3 coding sequence. The objective was to explore genetic variations of the FUT3 gene within the Han population of Northern China. A cohort of 313 blood donors was recruited for the study. The coding sequence of the FUT3 gene was amplified using polymerase chain reaction, followed by sequencing and haplotype construction. Twelve single nucleotide variations (SNVs) were identified within the coding sequence of the FUT3 gene. Notably, the c.59 T > G site exhibited the highest mutation frequency of 43.13%, followed by the c.508G > A and c.1067 T > A sites with mutation frequencies of 27.48% and 16.93%, respectively. Le was the most common haplotype, accounting for 67.57% of the cases, and Le/Le was the most common diplotype, accounting for 46.33% of the cases. The study also highlighted a significant difference in mutation frequencies of FUT3 gene between the Han Chinese of Northern China and the Dai of Xishuangbanna, China, but not the Han Chinese in Beijing in the North and the Southern Han Chinese, emphasising that Han Chinese in Northern China are genetically most distant from Europeans and closest to East Asians. Our study characterises FUT3 gene variations in Han Chinese from Northern China, and provides basic genetic data for genetics, forensic medicine, and genotyping of Lewis blood groups.

A [formula omitted] adic approach to the TSPO gene

TSPO protein is known to be involved in various cellular functions and dysregulations of TSPO expression has been found to be associated with pathologies of different human diseases, including cardiovascular disease, cancer, neuroinflammatory, neurodegenerative, neoplastic disorders. However, there are limited studies in the literature on the effects of sequence variations in the TSPO gene on the function of the protein and their relationship with human diseases. Evaluating the pathogenicity of genetic variants is crucial in terms of prioritizing the functional importance and clinical use. Therefore, various in-silico prediction tools have been developed that combine different algorithms to predict the effects of sequence variations on protein functions or gene regulation. In this study, the p-adic distance approach in modeling the genetic code, proposed and developed by Dragovich and Dragovich, was discussed in order to obtain an alternative to the existing in-silico prediction tools. Dragovichs’ approach is expressed as follows: A 5-adic space of codons is constructed and 5-adic and 2-adic distances between codons are taken into account. As a result, two codons with the smallest value of 5-adic and 2-adic distances are obtained, encoded for the same amino acid and stop signal. This model describes well the degeneration of the genetic code. This study combined the data obtained from in-silico prediction tools and used a bioinformatics approach to determine the functional relevance of coding SNPs in the TSPO. Overall, we evaluate the potential utility of Dragovichs’ approach by comparing it with other existing prediction tools for variant classification and prioritization.

Functional control of myosin motors in the cardiac cycle.

Contraction of the heart is driven by cyclical interactions between myosin and actin filaments powered by ATP hydrolysis. The modular structure of heart muscle and the organ-level synchrony of the heartbeat ensure tight reciprocal coupling between this myosin ATPase cycle and the macroscopic cardiac cycle. The myosin motors respond to the cyclical activation of the actin and myosin filaments to drive the pressure changes that control the inflow and outflow valves of the heart chambers. Opening and closing of the valves in turn switches the myosin motors between roughly isometric and roughly isotonic contraction modes. Peak filament stress in the heart is much smaller than in fully activated skeletal muscle, although the myosin filaments in the two muscle types have the same number of myosin motors. Calculations indicate that only ~5% of the myosin motors in the heart are needed to generate peak systolic pressure, although many more motors are needed to drive ejection. Tight regulation of the number of active motors is essential for the efficient functioning of the healthy heart - this control is commonly disrupted by gene variants associated with inherited heart disease, and its restoration might be a useful end point in the development of novel therapies.