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Objective: Allergic asthma is the most frequently observed subtype of individuals with asthma. The effects of serotonin plays in the pathophysiology of asthma has not been clearly determined. Thus, this study aimed to investigate the association between the 5HTR2C gene rs 6318 G>C polymorphism and allergic asthma in pediatric patients in Cyprus. Methods: This study included total number of 177 individuals with 118 control and 59 pediatric patients (43 atopic and 16 non-atopic asthma patient). A skin prick test was performed for each patient to confirm asthma diagnosis and to evaluate atopic status. Genotyping for the 5HTR2C was completed by Real Time-PCR analysis. Results: The genotype distribution frequencies were not in agreement with the Hardy-Weinberg Equilibrium in the patients’ group (p Discussion & Conclusion: Overall, despite the finding of no association between the 5HTR2C rs6318 C allele and childhood asthma, the current results indicated that there is a strong association between the 5HTR2C rs6318 C variant and childhood atopic asthma.

Vitiligo is a chronic autoimmune progressive dermatological disease and stress known to have impact on the development of vitiligo. However, the effect of serotonin has not been clearly explained for disease progression. Therefore, this study aimed to clarify stress induced 5-HTR2C rs6318 variant and its association with vitiligo pathogenesis. Study conducted with 108 vitiligo patients and 107 age-sex matched, unrelated healthy subjects as control group. Real Time-PCR analysis method was used for genotyping the 5-HTR2C variation. Genotype and allele frequencies considered for both control and patient groups. Genotype distributions for the Hardy-Weinberg Equilibrium (HWE) were analyzed. Vitiligo-related risk measures of different genotype combinations examined. Genotype correlations of the variant also analyzed based on gender difference, age onset of vitiligo, Koebner phenomenon history, clinical subgroups, treatment types, presence of other autoimmune diseases, vitiligo presence in family members and other autoimmune diseases in relatives. No statistically significant difference in 5HT-R2C receptor genotypes and allele frequencies between patient and control has been found. Genotype frequencies were not in agreement with the Hardy-Weinberg Equilibrium in the patients’ group (p 5-HTR2C variant rs6318 and vitiligo, the current results indicated that there is a strong association between the 5HTR2C rs6318 variant C allele and early age onset vitiligo development.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis.This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a subset of cases (n=4092). This subgroup was age and gender matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank.The ratio of males (31.08%; 27.01%) and the mean age (36.85±15.20; 33.89±14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p0.05). FVL prevalence, CT positivity rate, history of thrombosis, and Pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p0.05). Disease severity was mainly affected by Factor V Leiden and not related to genotypes at the Prothrombin mutations.Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients. This article is protected by copyright. All rights reserved.

Being one of the leading causes of cancer deaths worldwide and their resistance to conventional treatment methods, made gastrointestinal stromal tumors (GISTs) one of the hot topics in medical research areas in the past decade. To investigate molecular alterations underlying the tumor is of great importance to be able to develop new, targeted treatment options. In this study, GIST samples obtained from 40 Turkish patients were analyzed for actionable epidermal growth factor receptor (EGFR) mutations that are related to treatment regimes in non small cell lung cancer (NSCLC) to understand whether EGFR expression is altered in GISTs. Established alterations in EGFR can make the use of tyrosine kinase inhibitors possible, which are currently used in cancer therapy, especially in NSCLC. Our results indicated that EGFR mutations are rare in GISTs. Further research is needed to sequence whole coding regions of the gene to investigate new actionable mutations in EGFR in an increased sample size.

Objectives: Vitamin D is a fat-soluble, prohormone vitamin that is important especially for bone mineralization and skeletal health. In recent years, vitamin D deficiency appeared as a worldwide problem, affecting many people in different ways including the Northern Cypriot population. The deficiency might be caused by the lack of exposure to sunlight, diet low in vitamin D, sedentary lifestyle, and also due to some genetic variations in the vitamin D receptor (VDR) gene. Methods: In this study, four common VDR polymorphisms and associations with vitamin D deficiency in the Turkish Cypriot population between ages 18-40 and working in office conditions was studied by PCR- RFLP analysis. Results: rs2228570 C>T variant was shown to be significantly associated with low serum vitamin D levels in the studied population. Conclusion: Together with the effect of rs2228570 C>T variant in the VDR gene, it is thought that the lifestyle changes in the Turkish Cypriot population might have caused the increased frequency of vitamin D deficiency in the young professionals.

BACKGROUND Breast Cancer is the most common cancer type in women, second among the all cancers, and inherited with autosomal dominant pattern. The clinical diagnosis of BC relies on the published diagnostic criteria, and two genes have been identified as the main causative for breast cancer which are BRCA1 and BRCA2. OBJECTIVE We aimed to compare the index cases with the diagnostic features to describe the genotype/demographic information association in breast cancer. METHODS We performed mutational analyses for the BRCA1 and BRCA2 genes on 2475 individuals from collobrative centers across Turkey, whom 1444 of them were ascertained index cases. RESULTS We identified mutations in 17% (421/2475) of all individuals while its almost the same 16.6% (239/1444) in 1444 index cases. Mutations in BRCA1/BRCA2 genes were detected in 17.8% (131/737) of familial cases and 12% (78/549) of sporadic breast cancer, with 4.9% of mutations in the BRCA1 and 12% in the BRCA2. CONCLUSIONS Genotype variation and demographic information patterns were analyzed of all observed breast cancer findings in probands. We showed that patients with BRCA2 mutations have significantly been identified more than BRCA1 mutations. We also observed that sporadic breast cancer cases without familial history have less mutation positivity in BRCA1/BRCA2 genes, and the results were consistent with other studies in the Mediterranean region. On performing meta-analyses of our data and the other limited studies of the Mediterranean region in the literature, we found significant correlations that individual studies did not have sufficient power to conclude. Correlating genotypes with demographic information should facilitate the disease management of BC both the familial and non-familial cases.

Achondroplasia (ACH) is a hereditary disorder of dwarfism that is caused by the aberrant proliferation and differentiation of chondrocyte growth plates. The common findings of macrocephaly and facial anomalies accompany dwarfism in these patients. Fibroblast growth factor receptor 3 (FGFR3) gene mutations are common causes of achondroplasia. The current study presents a case of 2-year-old male child patient presenting with phenotypic characteristics of ACH. The interesting finding of the case is the presence of psychomotor delay that is not very common in these patients. Clinical exome sequencing analyzing 4.813 disease causing genes revealed a de novo c.1138G > A mutation within the FGFR3 gene. In conclusion, the mutation confirms the clinical diagnosis of ACH, and it seems to be causing the psychomotor delay in this patient.

Next-generation sequencing technology and advanced sequence analysis techniques are markedly speeding up the identification of gene variants causing rare genetic diseases. Pseudoachondroplasia (PSACH, MIM 177170) is a rare disease inherited in an autosomal dominant manner. It is known that variations in the cartilage oligomeric matrix protein (COMP) gene are associated with the disease. Here, we report a 39-month-old boy with short stature. He gave visible growth and development delayed phenotype after 12 months. Further genetic resequencing analysis was carried out to identified the disease-causing variant. Furthermore, computational approaches were used to characterize the effect of the variant. In this study, we identify and report a novel variation in the COMP gene, c.1420_1422del (p.Asn47del), causing a spontaneous form of PSACH in our patient. Our in silico model indicated that any mutational changes in this region are very susceptible to PASCH phenotype. Overall, this study is the first PSACH case in the Turkish Cypriot population. Moreover, this finding contributes to the concept that the genotype-phenotype correlation in COMP is still unknown and also improves our understanding of this complex disorder.

SummaryPolycystic ovarian syndrome (PCOS) is a chronic hormonal turmoil that is demonstrated in 2.2−27% of women of pre-menopausal age. This disease is a complex multigenic disorder that results from the interaction between excess androgen expression, genetic susceptibility and environmental influences. PCOS is associated with 40% of female infertility and endometrial cancer. The WNT/β-catenin signalling transduction pathway regulates aspects of cell proliferation, migration and cell fate determination in the tissue along with early embryonic development and controls the proper activation of the female reproductive system, along with regulating hormonal activity in ovarian granulosa cells. In the current study, we investigated the expression profiles of WNT/β-catenin signalling pathway genes (AXIN2, FZD4, TCF4, WNT3, WNT4, WNT5A, WNT7A, WNT1, APC, GSK3B and β-catenin) in a total of 13 oocyte samples. Seven of these samples were from polycystic women and six were from healthy women. The results of this study displayed the absence of expression of AXIN2, FZD4, TCF4, WNT5A, WNT3, WNT4 and WNT7A genes in ovaries from women with PCOS and from healthy women. While APC and β-catenin expression levels were similar in the oocytes of both patients and controls, conversely, WNT1 and GSK3β genes both showed elevated expression in the oocytes of patients with PCOS, therefore suggesting an association between aberrant expression of WNT1 and GSK3β and the pathogenesis of PCOS. The observations of the current study could be helpful to provide evidence regarding the pathogenesis of PCOS and its treatment.

Pathogenic variants in the coding regions of the BRCA1/2 lead dysfunctional or nonfunctional BRCA proteins however the contribution of non-coding BRCA1/2 variants to BRCA-related disease risk has not been fully elucidated. Thus, we characterized the functional impact of both coding and non-coding BRCA1/2 variants identified in individuals with personal and/or family history of BRCA-related cancers. The data were produced by resequencing the exons and exon-intron junctions of the BRCA1/2 in 125 individuals and were comprehensively analyzed by using bioinformatics tools and databases. A total of 96 variants (59 coding and 37 non-coding) including 7 novel variants were identified and analyzed for their functional importance. We identified 11 missense variants that potentially affect protein function; 22 variants were likely to alter different types of posttranslational modifications. Also, multiple non-coding BRCA1/2 variants were found to reside in the critical regulatory regions that have the potential to act as eQTLs and affect alternative splicing. The results of our study shed light on the possible contributions of not only coding variants but also non-coding BRCA1/2 variants in BRCRA-related cancers. Further investigation is required to fully understand their potential associations with phenotypes which may ultimately lead their utilization on cancer management as a biomarker.

Objectives Fructose-1,6-bisphosphatase deficiency (FBPase deficiency, OMIM 229700) is an early-onset rare genetic disorder caused by mutations in the FBP1 gene. Case presentation Our patient was 17-years-old when she was diagnosed with the disease. Initial sequencing analysis with Ion Torrent technology failed to detect the gross deletion that covered complete exon 2 (c.-24-26_170 + 5192del) of FBP1 gene and caused the delay in diagnosis. Deletion was then detected when sequencing was performed in an Illumina MiSeq platform. Conclusions This case emphasizes the importance of sequencing data analysis for precise diagnosis of rare diseases and therapy planning.

Trichorhinophalangeal syndrome (TRPS) is an extremely rare autosomal dominant multisystem disorder characterized by craniofacial and skeletal abnormalities. Three subtypes of TRPS have been described: TRPS type I, TRPS type II, and TRPS type III. Mutations in the TRPS1 gene can cause both TRPS type I and TRPS type III. Therefore, the genotype-phenotype correlation is crucial to determine the subtype. The current family study from Cyprus involves affected patients from 4 generations who presented with alopecia, unoperated umbilical hernia, caput quadratum, long philtrum, depressed nasal bridge, frontal bossing, pes planus, beaked nose, and some deformities in hands and feet. Sequence analysis of the TRPS1 gene revealed a novel c.2854_2858del (p.Asn952ArgfsTer2) frameshift variant leading to a premature stop codon. To the best of our knowledge, we report here the first case of a Turkish Cypriot family of 4 generations with a novel frameshift mutation leading to truncated protein in the TRPS1 gene causing TRPS type I clinical phenotype. Overall, as the genotype and phenotype correlation in TRPSI is still uncertain and complex, the present outcome can enhance our knowledge of this complicated, rare, and severe genetic disorder.

Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive–compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G&gt, A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C&gt, T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G&gt, A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C&gt, T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome.

Peeling skin syndrome is a heterogeneous group of rare disorders. Peeling skin, leukonychia, acral punctate keratoses, cheilitis and knuckle pads (PLACK syndrome, OMIM616295) is a newly described form of PSS with an autosomal recessive mode of inheritance. We report a 5.5-year-old boy with features of PLACK syndrome. Additionally, he had mild cerebral atrophy and mild muscle involvements. Whole exome sequencing was performed in genomic DNA of this individual and subsequent analysis revealed a homozygous c.544G > T (p.Glu182{*}) nonsense mutation in the CAST gene encoding calpastatin. Sanger sequencing confirmed this variant and demonstrated that his affected aunt was also homozygous. Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals. This study further supports a key role for calpastatin in the tight regulation of proteolytic pathways within the skin.

Vitamin D is an important molecule to keep teeth, bones and muscles healthy. It is obtained from diet, supplements and primarily from exposure to sunlight. In recent years, vitamin D deficiency is recognised as a worldwide health problem, which results in disturbances in mineral metabolism and skeletal problems. Deficiency might be caused due to sedentary lifestyle, insufficient diet, age as well as some polymorphisms in the VDR gene. In this study the four most common VDR polymorphisms (rs1544410 (BsmI), rs731236 (TaqI), rs7975232 (ApaI) and rs2228570 (FokI)) are investigated in a cohort of Turkish Cypriots and aimed to detect any possible links between low serum vitamin D levels and these variants. The rs2228570 (FokI) variant but not others were shown to have a significant association with decreased serum vitamin D levels in the Turkish Cypriot population.

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.

Impaired meiosis can result in absence of sperm in the seminal fluid. This condition, namely non-obstructive azoospermia (NOA), is one of the reasons of male infertility. Despite the low number of studies on meiosis 1-associated protein (We firstly performed an evolutionary conservation analysis for the variant positions. Afterwards, a comprehensive molecular modelling study was performed for the M1AP structure. By utilizing this model, protein dynamics were sampled for the wild-type and variants by performing molecular dynamics (MD) simulations.All variant positions are highly conserved, indicating that they are potentially important for function. In MD simulations, none of the variants led to a general misfolding or loss of stability in the protein structure, but they did cause severe modifications in the conformational dynamics of M1AP, particularly through changes in local interactions affecting flexibility, hinge and secondary structure.Due to critical perturbations in protein dynamics, we propose that these variants may cause NOA by affecting important interactions regulating meiosis, particularly in wild-type M1AP deficiency since the variants are reported to be homozygous or bi-allelic in the infertile individuals. Our results provided reasonable insights about the M1AP structure and the effects of the variants to the structure and dynamics, which should be further investigated by experimental studies to validate.

ObjectiveWe aimed to evaluate frequency and distribution MEFV gene mutation variants in patients with presumptive diagnosis of Familial Mediterranean Fever (FMF). Material and Methods Patients who had undergone FMF targeted mutation analysis between September 2018 and September 2019 were retrospectively analyzed. Twenty-six distinct MEFV gene mutation variants were studied. Demographic and clinical data of study participants were collected from patient charts and hospital electronic database system. Results Out of 910 referred patients, 350 (38.5%) were found to have a positive FMF mutation. In total, we detected 41 different genotypes and 26 different mutations in MEFV gene. The most common mutation and genotype were M694V and heterozygous M694V, respectively. Two hundred and seventy-six patients (78.9%) had a single mutation. Seventy-four patients had compound heterozygous mutation (21.1%). The most common compound heterozygous mutation was P369S/R408Q (23.3%). Five founder mutations constituted the seventy-five percent of the all mutations detected. Rare mutations that generally not examined in other studies were present in 15 patients (%4.2) in the form of two different compound heterozygous genotype. The total allele frequency of these rare mutations was 5%.Conclusion In this study, we examined an extended panel of MEFV mutations and detected more complex genotypes than most of the previous studies conducted in Turkish patients in the literature., AmaçAilesel Akdeniz Ateşi (FMF) olası tanısı olan hastalarda MEFV gen mutasyon varyantlarının sıklığı ve dağılımını değerlendirmeyi amaçladık.Gereç ve YöntemEylül 2018 ve Eylül 2019 arasında FMF hedef mutasyon analizi yapılan hastalar retrospektif olarak incelendi. Yirmi altı farklı MEFV gen mutasyon varyantı incelendi. Çalışma katılımcılarının demografik ve klinik verileri hasta listelerinden ve hastane elektronik veri tabanı sisteminden toplanmıştır.BulgularRefere edilen 910 hastanın 350'sinde (%38.5) FMF mutasyonu pozitif bulundu. Toplamda, MEFV geninde 41 farklı genotip ve 26 farklı mutasyon tespit ettik. En yaygın mutasyon ve genotip sırasıyla M694V ve heterozigot M694V idi. İki yüz yetmiş altı hastada (%78.9) tek bir mutasyon vardı. Yetmiş dört hastada bileşik heterozigot mutasyon vardı (%21.1). En yaygın bileşik heterozigot mutasyon P369S/R408Q (%23.3) idi. Beş kurucu mutasyon, tespit edilen tüm mutasyonların yüzde yetmiş beşini oluşturdu. Genel olarak diğer çalışmalarda incelenmeyen nadir mutasyonlar 15 hastada (% 4.2) iki farklı bileşik heterozigot genotip formunda mevcuttu. Bu nadir mutasyonların toplam alel sıklığı %5 idi. SonuçBu çalışmada, MEFV mutasyonlarının genişletilmiş bir panelini inceledik ve literatürde Türk hastalarda yapılan önceki çalışmaların çoğundan daha kompleks genotipler tespit ettik.

In this study, sweetened black and green tea were utilized as substrate for kombucha fermentation. Linden, lemon balm, sage, echinacea, mint, and cinnamon infusions were added to kombucha to design a novel beverage with Unproved functional and organoleptic characteristics. After fermentation, the antioxidant capacity (AC) of the kombucha increased by 13.96% 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 48.90% ferric reducing antioxidant power (FRAP), and 55.54% cupric reducing AC (CUPRAC). On days 0 and 9 of storage, the bioaccessibility of the total phenolics and AC (FRAP and CUPRAC) in all of the samples showed a significant increase after gastric and intestinal digestion when compared to pregastric digestion (P < 0.05). The AC (DPPH) after in vitro digestion at the beginning and end of storage in all of the beverages also increased after gastric digestion when compared to pregastric digestion (P < 0.05); however, it decreased after intestinal digestion (P < 0.05). By conducting in vitro and in vivo studies, the effects of kombucha on health and nutrition need to be further investigated.

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.

Aim Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) is the definition of a genetically heterogeneous group of diseases characterized by the impaired function of peripheral nerves. The aim of this study was to investigate the genetic etiology of CMT. Material and methods We herein examined 55 non-related patients with a suspicion of CMT phenotype or HMSN using a customized multigene panel based on the next-generation sequencing technique. All cases were previously analyzed for PMP22 duplication with the Multiplex Ligand Probe Amplification (MLPA) method. Results In 13 cases (7.15%), we identified a pathogenic/likely pathogenic variants. The affected genes were MARS1, NDRG1, GJB1, GDAP1, MFN2, PRX, SH3TC2, and FGD4. In six cases (10.9%), novel variants were identified: pathogenic variants in GJB1 and FGD4 genes, variants of unknown significance (VUS) in HSPB3, CHRNA1, ARHGEF10, and KIF5A genes. In 21 cases (11.55%), VUS with the genes HSPB3, KIF1B, SCN11A, CHRNA1, HSPB1, FIG4, ARHGEF10, DHTKD1, SBF1, EGR2, SBF2, IGHMBP2, KIF5A, and DNAJB2 were identified. Conclusion In this study, we had a 7.15% diagnosis rate with the NGS (Next Generation Sequencing) method in the CMT disease. Targeted next-generation sequencing panels are beneficial, time-saving, and cost-effective in the diagnosis of CMT.

Personalized medicine holds promise to tailor the treatment options for patients' unique genetic make-up, behavioral and environmental background. Liquid biopsy is non-invasive technique and precise diagnosis and treatment approach. Significantly, NGS technologies have revolutionized the genomic medicine by novel identifying SNPs, indel mutations in both coding and non-coding regions and also a promising technology to accelerate the early detection and finding new biomarkers for diagnosis and treatment. The number of the bioinformatics tools have been rapidly increasing with the aim of learning more about the detected mutations either they have a pathogenic role or not. EGFR, ROS1 and ALK genes are members of the RTK family. Until now, mutations within these genes have been associated with many cancers and involved in resistance formation to TKIs. This review article summarized the findings about the mostly investigated variations in EGFR, ROS1 and ALK genes and their potential role in liquid biopsy approach.

KUTUK, OZGUR/0000-0001-9854-7220; OZTOP, SIDIKA/0000-0001-5653-6080 WOS: 000567421400001 PubMed: 32901335 Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer. TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [113S871]; Baskent University Research FundsBaskent University; Science Academy BAGEP program This study was supported by TUBITAK 113S871 and Baskent University Research Funds. Ozgur Kutuk acknowledges support from the Science Academy BAGEP program.

Birt-Hogg-Dube syndrome (BHDS) is a rare disorder characterized by the triad of cutaneous lesions, renal tumors, lung cysts and inactivation of the gene folliculin (FLCN). Here, we present three female patients diagnosed with BHDS. First case a 55-year-old female had flesh moles histopathology compatible with angiofibroma, multiple cysts in the lung and kidneys, FLCN gene mutations ('c.1285dupC [p.His429Profs*]' 11th exon and 'c.653G>A [p.Arg258His]' 7th exon). The second case a 76-year-old female had trichodiscoma on her skin, multiple cysts in the lung, spontaneous pneumothorax, FLCN gene mutation 'c.1285dupC (p.His429Profs*27) 11th exon' and, her son had renal carcinoma history under 50 years of age. Our third case, also the daughter of case 2, had dermal papules histopathology compatible with trichodiscoma, spontaneous pneumothorax, FLCN gene mutation 'c.1285dupC (p.His429Profs*27) 11th exon' and, parotid oncocytoma. Through our cases, we document the first case of two mutations ('c.1285dupC [p.His429Profs*]' 11th exon and 'c.653G>A [p.Arg258His]' 7th exon) in the same FLCN gene and the 11th known case of parotid oncocytoma associated with BHDS in the light of the literature., NA

Background: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients. Case presentations: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. beta-blocker therapy was initiated to all the index subjects. Conclusions: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations., Ministry of Science, Industry and Technology

Neonatal progeroid syndrome or Wiedemann–Rautenstrauch syndrome (WRS; MIM 264090) is a rare genetic disorder that has clinical symptoms including premature aging, lipodystrophy, and variable mental impairment. Until recently genetic background of the disease was unclear. However, recent studies have indicated that WRS patients have compound heterozygote variations in the POLR3A (RNA polymerase III subunit 3A; MIM 614258) gene that might be responsible for the disease phenotype. In this study we report a WRS patient that has compound heterozygote variations in the POLR3A gene. One of the reported variations in our patient, c.3568C>T, p.(Gln1190Ter), is a novel variation that was not reported before. The other variant, c.3337-11T>C, was previously shown in WRS patients in trans with other variations.

Background:The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits.Objective:A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population.Methods:A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP.Results:The allelic frequency and genotype distribution results of this study showed a strong association (PConclusion:This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

Male infertility affects ∼7% of men in Western societies, but its causes remain poorly understood. The most clinically severe form of male infertility is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been reported to cause germ cell arrest in males. To address this gap, whole exome sequencing was performed in 60 German men with complete meiotic arrest, and we identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 infertile men and detected the same homozygous variant c.676dup in a man with hypospermatogenesis predominantly displaying meiotic arrest. We also identified two Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a consanguineous Turkish family comprising five infertile men. M1AP is predominantly expressed in human and mouse spermatogonia up to secondary spermatocytes and previous studies have shown that knockout male mice are infertile due to meiotic arrest. Collectively, these findings demonstrate that both LoF and missense M1AP variants that impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia and male infertility. In view of the evidence from several independent groups and populations, M1AP should be included in the growing list of validated NOA genes.

In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.

Objective Recent genome-wide association studies have established that polymorphisms within CDKN2B-AS1 of chr9p21.3 locus increased susceptibility to coronary artery disease (CAD) or myocardial infarction. Common variants of CDKN2B-AS1 (including rs4977574 A>G and rs1333040 C>T) are determined to be directly associated with CADs in many populations worldwide and suggested biomarkers for the early detection of CAD. There is a lack of investigation for the association between CDKN2B-AS1 rs4977574 A>G and rs1333040 C>T genetic modifiers and CAD in a Turkish Cypriot population. The aim of the present study was to investigate the potential effects of these variants on susceptibility to developing CAD in a Turkish Cypriot population and their contribution to lipid metabolism. Methods Seventy-one patients with angiography-confirmed CAD were recruited to the CAD group, whereas 153 voluntary subjects without CAD symptoms were enrolled to the control group. Genotyping for the CDKN2B-AS1 gene polymorphisms was performed by polymerase chain reaction, followed by restriction fragment length polymorphism analysis. Results There is no statistical significant association observed between rs4977574 and rs1333040 single-nucleotide polymorphisms and two studied groups [odds ratio (OR): 0.763, p=0.185, 95% confidence interval (CI): 0.511-1.139 and OR: 1.060, p=0.802, 95% CI: 0.672-1.671, respectively]. However, rs2977574 G and rs1333040 T alleles-the risk alleles-were found to be associated with higher level of serum total cholesterol and lower level of high-density lipoprotein-cholesterol in the CAD group (p=0.019, p=0.006 and p=0.022, p=0.031, respectively). To our knowledge, this is the first study that establishes the effect of rs1333040 on lipid metabolism. Conclusion The presence of rs4977574 G and rs1333040 T alleles and interaction may exist as environmental factors associated with lipid metabolism and might be responsible for the development of CAD in a Turkish Cypriot population.

Mutations in the gene for fibroblast growth factor receptor 3 (FGFR3) are implicated in achondroplasia, an autosomal-dominant form of short-limbed dwarfism. The present study involves a combination of clinical exome sequencing, targeted resequencing and protein modeling methods to decipher the pathobiology of achondroplasia with psychomotor delay in a two-year-old child. Accordingly, the resulting genetic information establishes the frequent FGFR3 c.1138G > A (p.G380R) mutation as the single hit causing pediatric achondroplasia with psychomotor delay, while the predicted model stresses the importance of a phenylalanyl residue (F384) in enhancing the dimerization potential of the receptor’s transmembrane domain via a cation‒π interaction with the newly introduced arginyl residue. Overall, the likely involvement of FGFR3G380R in psychomotor delay calls for comprehensive clinical assessment in achondroplastic children, although the precise mechanism by which the mutant receptor results in the development of neurological manifestations awaits further investigation.

Potassium channels are important in transmitting electrical signals through potassium ions transport. These potassium channels are made from signals encoded by KCNQ1 gene. KCNQ1 polymorphisms were associated with many diseases, including many metabolic and cardiovascular diseases and therefore they can be employed as biomarkers. In this study we aimed to investigate KCNQ1 polymorphisms in the Turkish Cypriot population to reveal the allele frequencies specific for this population and use these polymorphisms as biomarkers to develop preventative medical measures. The genotypes of KCNQ1 polymorphisms (rs231361, rs231359, rs151290, rs2283228, rs2237895, rs2237896) were investigated for the first time in Turkish Cypriot population. The correlation between genotypes of these polymorphisms and plasma lipid levels in this population was also explored. The results of this study showed that there was significant differences of the allele frequencies of between rs2283228 allele of C and rs2237896 (P > 0.05) in Turkish Cypriot population. There was no association between the genotypes of the six polymorphisms and the lipid metabolism. This study is the first genetic epidemiology study that investigated the allelic frequencies of KCNQ1 polymorphisms associated with metabolic syndromes as well as cardiovascular diseases. This study proves to be crucial since the etiologic determinants and molecular pathology of cardiovascular diseases have not yet clearly understood. This study showed that genome wide association studies should be designed for preventative medicine in the Turkish Cypriot population.

The ACE INDEL gene polymorphisms are strongly associated with CAD. Therefore, the present study was undertaken to investigate the relationship between ACE INDEL polymorphism and CAD in Turkish Cypriots whose are expected to have Mediterranean-style diet. 273 Turkish Cypriot descent volunteer subjects (186 controls and 87 CAD patients) participated in this study. Genotyping for the ACE INDEL polymorphism was performed by PCR-RFLP analysis. Biochemical parameters except the glucose and triglyceride lipid level were all within normal limits. Glucose level was found significant (p = 0.019) and triglyceride level was observed at the borderline for significance (p = 0.050) in participants according to WHO guidelines. With the respect to the genotype and allele distributions of ACE INDEL, the results showed statistically significant in CAD patients (p = 0.034) and not significant (p = 0.190) in controls. Haplotype analysis showed that D allele was more frequent in patients compared to controls. Thus, there is a statistically significant association with CAD disease with DD genotypes (p = 0.030) in Turkish Cypriot population. The results indicated that ACE INDEL polymorphism is an important predictor of coronary artery disease in Turkish Cypriots. Although 47% of the studied Turkish Cypriot population carry the D allele (p = 0.07), protocols should be developed for prevention strategies immediately.

Marfan syndrome (MFS) is a multi-systemic autosomal dominant condition caused by mutations in the gene (FBN1) coding for fibrillin-1. Mutations have been associated with a wide range of overlapping phenotypes. Here, we report on an extended family presenting with skeletal, ocular and cardiovascular clinical features. The 37-year-old male propositus, who had chest pain, dyspnea and shortness of breath, was first diagnosed based on the revised Ghent criteria and then subjected to molecular genetic analyses. FBN1 sequencing of the proband as well as available affected family members revealed the presence of a novel variant, c.7828G>C (p.Glu2610Gln), which was not present in any of the unaffected family members. In silico analyses demonstrated that the Glu2610 residue is part of the conserved DINE motif found at the beginning of each cbEGF domain of FBN1. The substitution of Glu2610 with Gln decreased fibrillin-1 production accordingly. Despite the fact that this variation appears to be primarily responsible for the etiology of MFS in the present family, our findings suggest that variable clinical expressions of the disease phenotype should be considered critically by the physicians.

PubMed: 30058754 We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T > C variant in the 3?UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes. © 2018 Wiley Periodicals, Inc. Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK: 114Z829 Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK Sehime G. Temel, Department of Medical Genetics, Department of Histology and Embryology, Faculty of Medicine, Uludag? University, Gorukle Campus, 16059 Nilufer, Bursa, Turkey Email: sehimegtemel@hotmail.com Aslıhan Tolun, Department of Molecular Biology andGenetics,Bog?aziçiUniversity,Istanbul, Turkey. Email: tolun@boun.edu.tr Funding Information This study was supported by the Scientific and Technological Research Council of Turkey (TÜBITAK) Grant 114Z829.

PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF.ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.GENETICS in MEDICINE advance online publication, 11 January 2018; doi:10.1038/gim.2017.253. ispartof: Genetics in Medicine vol:20 issue:10 pages:1236-1245 ispartof: location:United States status: published

Introduction: Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized by low adrenocorticotropic hormone (ACTH) and cortisol levels. To date, recurrent pulmonary infections in infancy have not been reported as an accompanying symptom of CIAD. Case Presentation: A 7-year-old boy was hospitalized nine times for recurrent lower respiratory tract infections. The results of all tests for the possible causes of wheezing were within the normal limits. His ACTH and cortisol levels were persistently low. All other pituitary hormone levels, and adrenal ultrasound and pituitary magnetic resonance imaging results, were normal. Molecular analyses confirmed the diagnosis of CIAD by identifying compound heterozygosity for two mutations in the TBX19 gene. The first was a novel frameshift c.665delG variant in exon 4 of TBX19 gene, leading to premature termination that was predicted to result in a non-functional truncated protein. The second was a nonsense C-to-T transition in exon 6 of the TBX19 gene, resulting in an arg286-to-ter mutation (dbSNP: rs74315376). Both parents were heterozygous for one of the mutations. Conclusions: Here, we presented a new mutation in the TBX19 gene in a patient with CIAD who presented with recurrent respiratory tract infections. This expands the mutation spectrum in this disorder. To conclude, adrenal insufficiency should be considered in patients with unexplained recurrent infections to prevent a delay in diagnosis. Keywords: Adrenal insufficiency; adrenocorticotropic hormone; cortisol; respiratory infections; TBX19 gene