Whole-Exome Sequencing in Turkish Patients with Inherited Retinal Dystrophies Reveals Novel Variants in Ten Genes.

Introduction: Inherited retinal dystrophies (IRDs) associated with more than 300 genes are a clinically and genetically heterogeneous group of retinal diseases. This study aimed to identify causative gene variants and molecular basis of Turkish patients with IRD. Methods: Whole-exome sequencing was performed in 28 unrelated patients. The potential pathogenicity of variants was evaluated using the American College of Medical Genetics variant interpretation guidelines, in silico prediction tools, published literature or Human Gene Mutation Database, and compatibility with inheritance patterns or known phenotypes. Results: Causative variants in 21 genes, including MERTK, SNRP200, MYO7A, AIPL1, RDH12, OTX2, ADGRV1, RPGRIP1, SPATA7, USH2A, MFSD8, CDHR1, EYS, CACNA1F, CNGA3, RDH5, TULP1, BBS2, BEST1, RS1, GUCY2D were detected in 26 (92.9%) of 28 patients. The most prevalent causative variants were observed MERTK (10.7% of cases), followed by CDHR1, AIPL1, RDH12, SPATA7, CNGA3, TULP1 (7.1% of cases, each). The most common variant type in this study was missense variants (53%), followed by frameshift (21%), nonsense (20%), and splice (6%). Twelve novel variants, 6 of frameshift and 6 of missense, were detected in ten genes. Retinitis pigmentosa was the most common phenotype followed by Leber congenital amaurosis. Conclusion: This study provides an overview of causative gene variants in Turkish patients with IRD. Variants identified in this study expand the variant spectrum of IRD genes. We believe it is essential to combine molecular and clinical data to diagnose IRD patients, especially with the emergence of therapeutic options.

Evaluation of cortical and trabecular bone structure of the mandible in patients with ankylosing spondylitis.

This study aimed to examine the difference between the fractal dimension (FD) values of the mandibular trabecular bone and the panoramic mandibular index (PMI), mandibular cortical index (MCI) and mandibular cortical thickness (MCW) of patients with ankylosing spondylitis (AS) and healthy control group. A total of 184 individuals (92 cases, 92 controls), were examined in our study. PMI, MCI, and MCW values were calculated on panoramic images of all individuals. For FD values, the region of interest (ROI) was selected with the size of 100 × 100 pixels from the right-left gonial and interdental regions and 50 × 50 pixels from the condylar region. Degenerative changes in the temporomandibular joint (TMJ) region were recorded. PMI, MCI, and MCW values showed statistically significant differences between the groups (p = 0.000, p < 0.001). The radiological signs of mandibular cortical resorption were more severe in the case group than in the control group. PMI and MCW values were found to be lower in the case group than in the control group. It was determined that the number of C3 and C2 values, among the MCI values, was higher in the case group. Only the FD values of the ROI selected from the condyle region were found to be statistically significant and were lower in the case group (p = 0.026, p < 0.05). Degenerative changes in the TMJ region were significantly more frequent in the case groups (p = 0.000, p < 0.001). The fact that the mandibular cortex shows more resorptive features in individuals with AS may require further evaluation in terms of osteoporosis. Because of the low FD values of the condylar regions of these patients and the more frequent degenerative changes, the TMJ region should be followed carefully. Detailed examination of the mandibular cortex and condylar region is beneficial in patients with AS for screening and following osteoporotic changes in these individuals, which is essential for the patient's life quality.

Assessment of whole-exome sequencing results in neurogenetic diseases.

Neurogenetic diseases are rare genetic diseases in which neurological findings are prominent. Whole exome sequencing (WES) has led to great advances in the understanding of the causes of neurogenetic diseases. Etiological research ends with the WES method in many patients. This etiological research is called a "diagnostic odyssey" for many families. Here, we present the results of 168 patients who were previously undiagnosed and underwent WES with the suspicion of neurogenetic disease. A total of 168 cases, 94 males and 74 females, with suspected undiagnosed neurogenetic disease were included in the study. We presented the WES results of the patients. The mean age of patients at the time of WES request was 11 years (range 0.25-68 years). Seventy percent (n = 117) of the patients were born from consanguineous marriage. Most of the patients were children (n = 145). Patients were grouped according to age at the time of examination. Patients younger than 18 years of age at the time of examination were classified as children, otherwise adults. Seventy-eight patients had either a pathogenic variant or a likely pathogenic variant so the diagnostic rate for WES in our cohort was %46. Our experience showing the high diagnostic rate of WES, supports its use in undiagnosed neurogenetic diseases. It also affects medical treatment, prognosis and family planning by enabling early diagnosis in patients.

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

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 group 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 (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL 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.

First report of the c.1676G>A homozygous variant in a family with Kindler syndrome.

Kindler syndrome (KS) was first described by Theresa Kindler in 1954, and since then > 60 pathogenic variants have been identified in the FERMT1 gene for KS. Most FERMT1 variants associated with KS are null variants. We present the case of a child with poikilodermic changes on the forehead and cheeks, who was found to have a homozygous c.1676G>A mutation. To our knowledge, this is the first report of this mutation in a family with KS.

Extended-spectrum of KRAS and NRAS mutations in lung cancer tissue specimens obtained with bronchoscopy.

Background: Mutations in the RAS genes, HRAS, KRAS, and NRAS, are the most common modifications in many types of human tumors and are found in approximately 30% of all human cancers. These mutations are usually found in codons 12, 13, or 61. Methods: The aim of this study is to evaluate mutations in codons 59, 117, and 146 of KRAS and NRAS genes in addition to codons 12,13, and 61 of KRAS gene in lung cancer tissue specimens obtained with bronchoscopy. KRAS and NRAS mutation analyses with pyrosequencing were performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue samples of 64 patients histopathologically diagnosed as lung cancer after bronchoscopic biopsy. Results: In all, 20 patients (31.2%) had mutations in KRAS gene (8/27 squamous cell carcinoma, 8/11 adenocarcinoma, 3/16 small cell carcinoma, and 1/1 pleomorphic carcinoma). The most common mutation in codon 12 was in c.35G>T (G12V). When the mutation rate of adenocarcinoma (72.7%) and squamous cell carcinoma (22.9%) patients was compared with each other, a statistically significant difference was observed (P = 0.008). There were no mutations in codons 59, 117, or 146 of KRAS and NRAS genes in patients with lung cancer. Conclusion: In this study, we firstly examined mutations in codons 59, 117, and 146 of KRAS and NRAS genes in addition to codons 12, 13, and 61 of KRAS gene in Turkish lung cancer patients both in non-small cell lung cancer and small cell lung cancer. Although no mutation was detected in codons 59, 117, and 146 of KRAS and NRAS genes, the frequency of KRAS gene mutation was higher than the rate of mutation in both Asian and Western countries, and multicenter studies including more cases should be performed to further explore our results.

Are Pattern Recognition Receptors Associated with Hepatocellular Carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the important causes of mortality due to malignancy. Toll-like receptors (TLRs) are very important in liver pathophysiology in terms of their roles in the innate immune system, such as the regulation of inflammation, wound healing, stimulation of adaptive immune responses, promotion of epithelial regeneration, and carcinogenesis. In this study, we planned to examine the role of TLR1 (rs4833095, rs5743551) and nucleotide-binding oligomerization domain (NOD2) (rs2066844, rs2066845, rs2066847) polymorphisms in the development of HCC and their effects on the clinical presentation of HCC patients. METHODS: Our study was designed prospectively. Cirrhotic and HCC patients who were followed up in our clinic between January 2015 and September 2018 were included in the study. Sex, age, cirrhosis etiology, Child-Pugh class, and MELD scores were recorded. TLR1 and NOD2 polymorphisms were studied by the PCR method. RESULTS: HCC developed in 88 (31.4%) of the 280 patients who were followed up, either during the recruitment phase of our study or during the follow-up. The mean follow-up time of our patient group was 17.04 ± 11.72 months, and the mean follow-up time of HCC patients was 12.09 ± 10.26 months. TLR1 (rs5743551) polymorphism was associated with HCC development (P = .003). TLR1 (rs5743551) and NOD2 (rs2066844) polymorphisms were associated with the development of spontaneous bacterial peritonitis (SBP) in the HCC patient group (P = .013 and P = .021, respectively). CONCLUSION: We think that increased bacterial translocation in cirrhotic patients may contribute to HCC development by causing chronic inflammation, especially in patients with TLR 1 (rs5743551) polymorphism.