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1.
Br J Haematol ; 205(1): 236-242, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38811201

RESUMO

Pyruvate kinase (PK) is a key enzyme of anaerobic glycolysis. The genetic heterogeneity of PK deficiency (PKD) is high, and over 400 unique variants have been identified. Twenty-nine patients who had been diagnosed as PKD genetically in seven distinct paediatric haematology departments were evaluated. Fifteen of 23 patients (65.2%) had low PK levels. The PK:hexokinase ratio had 100% sensitivity for PKD diagnosis, superior to PK enzyme assay. Two novel intronic variants (c.695-1G>A and c.694+43C>T) have been described. PKD should be suspected in patients with chronic non-spherocytic haemolytic anaemia, even if enzyme levels are falsely normal. Total PKLR gene sequencing is necessary for the characterization of patients with PKD and for genetic counselling.


Assuntos
Anemia Hemolítica Congênita não Esferocítica , Íntrons , Piruvato Quinase , Erros Inatos do Metabolismo dos Piruvatos , Humanos , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Masculino , Feminino , Erros Inatos do Metabolismo dos Piruvatos/genética , Criança , Pré-Escolar , Anemia Hemolítica Congênita não Esferocítica/genética , Turquia , Lactente , Adolescente , Mutação
2.
Clin Exp Immunol ; 209(1): 83-89, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35511492

RESUMO

STAT3 plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis. The transcriptional activity of the STAT3 gene is controlled by a transcription factor called ZNF341. There is insufficient data on radiation sensitivity and post-radiation DNA repair in STAT3- loss-of-function (LOF) patients. We aimed to investigate the radiosensitivity in patients with STAT3-LOF and ZNF341 deficiency. Twelve patients with STAT3-LOF and four ZNF341-deficiency patients were recruited from three clinical immunology centers in Turkey and evaluated for radiosensitivity by the Comet assay, comparing to 14 age- and sex-matched healthy controls. The tail length (TL) (µm), percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2 Gy irradiation), and recovery (2 h after irradiation) periods by using a computerized image-analysis system, estimating DNA damage. Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups. During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms. Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation.


Assuntos
Reparo do DNA , Tolerância a Radiação , Fator de Transcrição STAT3 , Fatores de Transcrição , Ensaio Cometa , Dano ao DNA/genética , Reparo do DNA/genética , Regulação da Expressão Gênica , Humanos , Mutação com Perda de Função , Tolerância a Radiação/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética
3.
Med Princ Pract ; 25(2): 155-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26535568

RESUMO

OBJECTIVE: To determine the role of glutathione S-transferase (GST) isoenzyme polymorphisms as susceptibility factors in patients with psoriasis in a Turkish cohort. SUBJECTS AND METHODS: In this case-control study, 105 patients with plaque-type psoriasis and 102 healthy controls were recruited from the dermatology outpatient clinics of two university hospitals. Genomic DNA was extracted from whole blood using a DZ DNA isolation kit. Multiplex PCR was used to determine GSTM1 and GSTT1 polymorphisms in the isolated DNAs. RESULTS: Of the 150 patients with psoriasis, 83 (79%) were identified with the GSTT1 genotype and 22 (21%) with the null genotype. Of the 102 patients in the control group, 69 (67.6%) subjects were identified with the GSTT1 genotype and 33 (32.4%) with the null genotype. There was no significant difference between the patient and control groups (p = 0.063). Regarding the GSTM1 polymorphism, 54 (51.4%) patients were identified with this genotype and 51 (48.6%) with the null genotype; in the control group, 50 (49%) were identified with this genotype and 52 (51%) with the null genotype. Again there was no statistically significant difference between the groups (p = 0.957). CONCLUSION: In this Turkish cohort of patients with psoriasis, neither GSTT1 nor GSTM1 polymorphisms were associated with disease susceptibility. Larger studies with a wider range of GST isoenzyme are needed.


Assuntos
Glutationa Transferase/genética , Polimorfismo Genético , Psoríase/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase , Fatores de Risco , Turquia
4.
Diagnostics (Basel) ; 14(6)2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38535054

RESUMO

Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever and serositis. Blood-based biomarkers determined in FMF patients during attack-free periods could be used to predict the risk of amyloidosis and the severity of the disease. The recently defined pan-immune-inflammation value (PIV) comprises four distinct subsets of blood cells and serves as an easily accessible and cost-effective marker. The objective of this study was to assess the role of PIV in predicting amyloidosis and moderate-to-severe disease. Clinical characteristics and laboratory values during the attack-free period were retrospectively analyzed in 321 patients over 18 years of age diagnosed with familial Mediterranean fever (FMF). In our tertiary adult rheumatology outpatient clinic, disease severity and laboratory markers were evaluated during the first attack-free interval. At baseline, patients with amyloidosis were excluded. Patients were categorized based on the presence of amyloidosis and the severity of the disease. When focusing on amyloidosis in receiver operating characteristic (ROC) analysis, optimal cut-off values for pan-immune-inflammation value (PIV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio were determined as ≥518.1, ≥2.3, and ≥127.2, respectively. In multivariate analysis, PIV, C-reactive protein (CRP), and the presence of the M694V homozygous mutation emerged as independent risk factors for both amyloidosis and moderate-to-severe disease. Additionally, NLR was identified as an independent risk factor for amyloidosis, while red blood cell distribution width was associated with moderate-to-severe disease. In patients with FMF, especially in the presence of the M694V homozygous mutation, CRP and PIV may be useful in predicting both amyloidosis and moderate-to-severe disease.

5.
Biomedicines ; 12(5)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38790930

RESUMO

Alzheimer's disease (AD) is a major global health challenge, especially among individuals aged 65 or older. According to population health studies, Turkey has the highest AD prevalence in the Middle East and Europe. To accurately determine the frequencies of common and rare APOE single nucleotide polymorphisms (SNPs) in the Turkish population residing in the Marmara Region, we conducted a retrospective study analyzing APOE variants in 588 individuals referred to the Bursa Uludag University Genetic Diseases Evaluation Center. Molecular genotyping, clinical exome sequencing, bioinformatics analysis, and statistical evaluation were employed to identify APOE polymorphisms and assess their distribution. The study revealed the frequencies of APOE alleles as follows: ε4 at 9.94%, ε2 at 9.18%, and ε3 at 80.68%. The gender-based analysis in our study uncovered a tendency for females to exhibit a higher prevalence of mutant genotypes across various SNPs. The most prevalent haplotype observed was ε3/ε3, while rare APOE SNPs were also identified. These findings align with global observations, underscoring the significance of genetic diversity and gender-specific characteristics in comprehending health disparities and formulating preventive strategies.

6.
J Clin Res Pediatr Endocrinol ; 15(3): 285-292, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37074225

RESUMO

Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center. Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records. Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83). Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up.


Assuntos
Síndrome de DiGeorge , Diabetes Mellitus Tipo 2 , Nanismo , Hipocalcemia , Hipoparatireoidismo , Humanos , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Hipocalcemia/diagnóstico , Hipocalcemia/genética , Cálcio , Hibridização in Situ Fluorescente , Diabetes Mellitus Tipo 2/genética , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/complicações , Hormônio Paratireóideo , Nanismo/genética , Deleção Cromossômica , Fósforo
7.
Eur J Breast Health ; 19(3): 235-252, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37415649

RESUMO

Objective: Breast cancer (BC) is the most common cancer type in women and may be inherited, mostly in an autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and analysis of two genes, BRCA1 and BRCA2, which are strongly associated with BC, are included in these criteria. The aim of this study was to compare BC index cases with non-BC individuals in terms of genotype and diagnostic features to investigate the genotype/demographic information association. Materials and Methods: Mutational analyses for the BRCA1/BRCA2 genes was performed in 2475 individuals between 2013-2022 from collaborative centers across Turkey, of whom 1444 with BC were designated as index cases. Results: Overall, mutations were identified in 17% (421/2475), while the percentage of mutation carriers in cases of BC was similar, 16.6% (239/1444). BRCA1/BRCA2 gene mutations were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic cases. Mutations in BRCA1 were found in 4.9%, whereas 12% were in BRCA2 (p<0.05). Meta-analyses were performed to compare these results with other studies of Mediterranean-region populations. Conclusion: Patients with BRCA2 mutations were significantly more common than those with BRCA1 mutations. In sporadic cases, there was a lower proportion with BRCA1/BRCA2 variants, as expected, and these results were consistent with the data of Mediterranean-region populations. However, the present study, because of the large sample size, revealed more robust findings than previous studies. These findings may be helpful in facilitating the clinical management of BC for both familial and non-familial cases.

8.
Eur J Hum Genet ; 30(3): 378-383, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35132179

RESUMO

Next-generation sequencing (NGS) is used increasingly in hereditary cancer patients' (HCP) management. While enabling evaluation of multiple genes simultaneously, the technology brings to light the dilemma of variant interpretation. Here, we aimed to reveal the underlying reasons for the discrepancy in the evidence titles used during variant classification according to ACMG guidelines by two different bioinformatic specialists (BIs) and two different clinical geneticists (CGs). We evaluated final reports of 1920 cancer patients and 189 different variants from 285 HCP were enrolled to the study. A total of 173 of these variants were classified as pathogenic (n = 132) and likely pathogenic (n = 41) by the BI and an additional 16 variants, that were classified as VUS by at least one interpreter and their classification would change the clinical management, were compared for their evidence titles between different specialists. The attributed evidence titles and the final classification of the variants among BIs and CGs were compared. The discrepancy between P/LP final reports was 22.5%. The discordance between CGs was 30% whereas the discordance between two BIs was almost 75%. The use of PVS1, PS3, PP3, PP5, PM1, PM2, BP1, BP4 criteria markedly varied from one expert to another. This difference was particularly noticeable in PP3, PP5, and PM1 evidence and mostly in the variants affecting splice sites like BRCA1(NM_007294.4) c.4096 + 1 G > A and CHEK2(NM_007194.4) c.592 + 3 A > T. With recent advancements in precision medicine, the importance of variant interpretations is emerging. Our study shows that variant interpretation is subjective process that is in need of concrete definitions for accurate and standard interpretation.


Assuntos
Predisposição Genética para Doença , Neoplasias , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Neoplasias/genética
9.
Genet Test Mol Biomarkers ; 25(1): 59-67, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33470886

RESUMO

Objective: Osteogenesis imperfecta (OI) includes a group of disorders characterized by susceptibility to bone fractures with different severities. The increasing number of genes that may underlie the disorder, along with the broad phenotypic spectrum that overlaps with other skeletal diseases, provided a compelling case for the use of high-throughput sequencing (HTS) technology as an aid to OI diagnoses. The aim of this analysis was to present the data from our 5-year targeted HTS results, that includes the reporting of 9 novel and 24 known mutations, found in OI patients, from 5 different regions of Turkey. Materials and Methods: We performed a retrospective cross-sectional study, reporting the HTS results of 43 patients (23 female and 20 male; mean age: 9.5 years), directed to our center with a suspicion of OI between February 2015 and May 2020. Genetic analyses were also performed for 24 asymptomatic parents to aid the segregation analyses. We utilized an HTS panel targeting the coding regions of 57 genes associated with a reduction, increase, or abnormal development of bone mineralization. In addition, we sequenced the entire coding region of the IFITM5 gene through HTS. Results: Thirty-nine patients had at least one pathogenic/likely pathogenic variation (90.69%) in the COL1A1 (56.41%), COL1A2 (20.51%), FKBP10 (7.7%), P3H1 (5.13%), IFITM5 (5.13%), CTRAP (2.56%), or TMEM38B (2.56%) genes. Nine of the determined pathogenic/likely pathogenic variations were novel. The recurrent pathogenic mutations were c.1081C>T (p.Arg361Ter) (3/43), c.1405C>T (p.Arg469Ter) (2/43), and c.3749del (p.Gly1250AlafsTer81) in COL1A1 gene, along with c.-14C>T variation in the 5'UTR of the IFITM5 gene (2/43) and the c.890_897dup variation in the FKBP10 gene (2/43). Three out of 43 patients were carrying at least one additional variant of unknown significance, highlighting the importance of a multigene panel approach and segregation analyses. Conclusion: We suggest that a targeted HTS panel is a feasible tool for genetic diagnosis of OI in patients.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Adolescente , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Retrospectivos , Turquia
10.
Genes (Basel) ; 12(11)2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34828379

RESUMO

Artificial intelligence provides modelling on machines by simulating the human brain using learning and decision-making abilities. Early diagnosis is highly effective in reducing mortality in cancer. This study aimed to combine cancer-associated risk factors including genetic variations and design an artificial intelligence system for risk assessment. Data from a total of 268 breast cancer patients have been analysed for 16 different risk factors including genetic variant classifications. In total, 61 BRCA1, 128 BRCA2 and 11 both BRCA1 and BRCA2 genes associated breast cancer patients' data were used to train the system using Mamdani's Fuzzy Inference Method and Feed-Forward Neural Network Method as the model softwares on MATLAB. Sixteen different tests were performed on twelve different subjects who had not been introduced to the system before. The rates for neural network were 99.9% for training success, 99.6% for validation success and 99.7% for test success. Despite neural network's overall success was slightly higher than fuzzy logic accuracy, the results from developed systems were similar (99.9% and 95.5%, respectively). The developed models make predictions from a wider perspective using more risk factors including genetic variation data compared with similar studies in the literature. Overall, this artificial intelligence models present promising results for BRCA variations' risk assessment in breast cancers as well as a unique tool for personalized medicine software.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Biologia Computacional/métodos , Variação Genética , Adolescente , Adulto , Idoso , Inteligência Artificial , Neoplasias da Mama/genética , Bases de Dados Genéticas , Feminino , Lógica Fuzzy , Humanos , Pessoa de Meia-Idade , Redes Neurais de Computação , Estudos Retrospectivos , Adulto Jovem
11.
Genet Test Mol Biomarkers ; 19(8): 461-4, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26154773

RESUMO

BACKGROUND: The roles of interleukin (IL)-17A and IL-17F in the pathogenesis of rheumatoid arthritis (RA) have been previously studied. However, the relationships between polymorphisms (IL-17A G197A, the IL-17F 7488A/G, and the IL-17F 7383A/G) of these genes with RA have not been clarified yet. AIMS: To investigate the impacts of these polymorphisms on the severity and susceptibility of RA in a Turkish population. METHODS: One hundred sixty-one patients with RA and 88 healthy sex-, age-, and ethnicity-matched controls were enrolled in this study. The erythrocyte sedimentation rate, C-reactive protein (CRP), and disease activity scores 28 (DAS28) of all participants were recorded. The IL-17A G197A, the IL-17F 7488A/G, and 7383A/G polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: We found no significant difference regarding genotypes or allelic frequency distributions of the IL-17A G197A, the IL-17F 7383A/G, and 7488A/G polymorphisms between patients and healthy controls (p>0.05). There were slight, but not significant, differences in terms of CRP levels associated with the distribution of the genotypes of the IL-17F 7488A/G, and regarding DAS28 levels according to the genotype distribution of the IL-17A G197A polymorphism (p=0.062, 0.087, 0.052, respectively). CONCLUSIONS: These findings suggest that future larger scale studies with increased power should be performed to determine if the IL-17F 7488A/G and the IL-17A G197A polymorphisms are associated with the disease activity in patients with RA.


Assuntos
Artrite Reumatoide/genética , Interleucina-17/genética , Adulto , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interleucina-17/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Turquia
12.
Genet Test Mol Biomarkers ; 19(10): 584-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26308792

RESUMO

AIMS: Fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (QRT-PCR) were used to diagnose or screen for minimal residual disease (MRD) in Philadelphia (Ph) chromosome-positive leukemia. We compared the diagnostic utility of FISH and QRT-PCR at various time points in the course of chronic myelogenous leukemia (CML) and to determine the mean initial values for patients whose QRT-PCR results were not known at the time of diagnosis. RESULTS: We analyzed 135 results for 78 CML patients tested by FISH and QRT-PCR for the Ph chromosomal translocation. All newly diagnosed cases were positive by both methods. On follow-up following treatment, 1 case was FISH positive and QRT-PCR negative; 61 cases were FISH negative and QRT-PCR positive. Overall concordance was 54.1%. There was good concordance between QRT-PCR results and cytogenetic response categories. CONCLUSIONS: We confirmed that QRT-PCR allows precise measurement of low levels of BCR-ABL transcripts and can serve as a sensitive indicator of MRD. We also demonstrated 100% correlation between QRT-PCR and FISH in newly diagnosed CML.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Feminino , Proteínas de Fusão bcr-abl/sangue , Humanos , Hibridização in Situ Fluorescente/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos Testes
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