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Objective: Ichthyosis is a clinically heterogeneous group of genodermatoses characterized by widespread drying and scaling of the skin. It is also a genetically heterogeneous disorder, and 67 genes associated with the disease have been identified to date. However, there are still undiscovered genes causing the disease., Methods: We investigated 19 Turkish patients from 17 unrelated families using clinical exome sequencing or multigene panel screening., Results: Sixteen likely pathogenic or pathogenic variants were detected in 13 unrelated patients. We identified "variant of unknown significance" alteration in only one patient. Seven novel variants were identified in ABCA12, ALOX12B , and ALOXE3 . The most commonly mutated gene was TGM1 , followed by ABCA12 and ALOX12B ., Conclusions: Because of the wide genetic variability of ichthyosis, it is difficult to diagnose the disease quickly and definitively. The clinical use of next-generation sequencing (NGS) methodologies is beneficial in the diagnostic approach to ichthyosis and genetic counseling. This study highlights the underlying molecular cause of ichthyosis by determining the mutational spectrum in a cohort of 19 patients. This study is the first and largest research from Turkey using NGS that highlights all ichthyosis subtypes., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare., (©Copyright 2022 by the Istanbul Medeniyet University / Medeniyet Medical Journal published by Galenos Publishing House.)

Objective: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases., Methods: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients., Results: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10)., Interpretation: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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Background: Inherited retinal dystrophies (IRDs) are a group of retinal diseases genetically and clinically highly heterogeneous and associated with more than 300 genes. This study aims to investigate the genetic basis of Turkish patients with IRDs., Materials and Methods: In the study, genes related to retinal diseases in 86 IRDs patients were analyzed using the Next Generations Sequencing method (NGS)., Results: The mean age of 86 patients was 35 and the mean age at diagnosis was 18. There was consanguinity between the parents of 62% of these patients. Fifty-six retinal disease-associated genes of 46 patients and 230 retinal disease-associated genes of 40 patients were examined. Genetic analysis provides a molecular diagnosis in a total of 53 (61.6%) patients. The genes responsible for the IRDs phenotype were frequently identified as ABCA4 (25%), EYS (11%), and RDH12 (9%). There was no significant difference between those with and without a molecular diagnosis in terms of demographic characteristics and family history., Conclusions: Determination of genetic cause by NGS method in IRDs subgroups that are difficult to define by ophthalmic examination ensures that patients receive accurate diagnosis, treatment and counseling. This study contributed to the understanding of the genotype-phenotype relationship of Turkish patients with IRDs.

Objective: To determine the diagnostic importance of using an exome-based multigene panel in childhood epilepsy., Study Design: Observational study., Place and Duration of Study: Department of Medical Genetics, Diskapi Yildirim Beyazid Training and Research Hospital, from January 2017 to May 2020., Methodology: The phenotype-genotype relationship was investigated in 35 pediatric patients (aged 18 years or younger) with epilepsy, using a large gene panel comprising 464 epilepsy-related genes. The exome-based panel was used to analyse secondary findings.   Results: The diagnostic yield of the targeted multi-gene panel used was 20% (7/35). The causative genes identified in seven patients (5 boys, 2 girls) were CACNA1E, RELN, PRRT2, TSC1, GABRG2, SCN2A, and SHH. Four of the detected disease-related variants were defined as the novel. Secondary findings in various genes were detected in 19 of the patients. Seven patients with causal genes and the remaining 28 patients were compared in terms of parameters such as gender, mental retardation, developmental retardation, autism, hypotonia, seizure phenotype (only), seizure phenotype (plus), magnetic resonance imaging, degree of kinship of their parents and number of relatives with epilepsy. In addition, patients were evaluated statistically in terms of the same parameters by grouping them according to their gender. There was no statistically significant difference in either study (p >0.05)., Conclusion: Genetic testing is an important tool for clinicians in determining the diagnosis, management, and treatment strategies of epilepsy patients. Key Words: Epilepsy, Diagnostic yield, Exome-based multigene panel, Next-generation sequencing, Seconder findings.

Objective: To investigate the genetic causes of colorectal cancers (CRCs); and to determine the genotype-phenotype correlation., Study Design: Descriptive study., Place and Duration of Study: Department of Medical Genetics, Diskapi Yildirim Beyazit Training and Research, Hospital, Ankara, Turkey, between January 2018 and January 2020., Methodology: 59 cancer susceptibility genes of 41 patients, included in the study and diagnosed with CRC, were examined using next generation sequencing (NGS) technique. Statistical analysis of the possible relationships among the mutation carrier status of the patients and the parameters of gender, age at diagnosis, and family cancer history, were performed., Results: The mean age at diagnosis of all CRC patients was 48.7 years (range 28-74). Mutations in MLH1, MSH6, CHEK2, PMS2 and MUTYH genes were detected in 10 patients (24.4%). The mean age at diagnosis of CRC was 46.2 years in those who carried the mutation, while it was 49.5 years in those without. Carriers and non-mutation carriers, when compared in terms of age at diagnosis, gender, family cancer history, no significant difference was observed., Conclusion: Genes that may cause susceptibility to cancer may play a role in the etiopathogenesis of the CRC. NGS-based multigene panels allow these genes to be detected in the patient and to identify an inherited cancer syndrome. Key Words: Colorectal cancer, Lynch syndrome, Hereditary cancer, Gene, Next generation sequencing.

Objective: BRCA1/2 genes play a role in the etiopathogenesis of 10%-30% of triple-negative breast cancer (TNBC). This study aims to investigate the BRCA1/2 genes and the demographic and clinicopathological features in patients with TNBC. The study also examined the impact of cancer history of TNBC individuals' relatives on the risk of BRCA1/2 mutation carriership rate., Materials and Methods: The BRCA1/2 genes of 65 women diagnosed with TNBC between 2011 and 2017 were investigated using next-generation sequencing. We analyzed the correlations of patients' demographic and clinicopathologic parameters and family history with BRCA1/2 mutation status. We used the χ 2 -test, t-test, Mann-Whitney U test, and logistic regression statistical methods., Results: The BRCA1/2 mutation carrier rate was 16.9%. Patients who had BRCA1/2 mutations were compared with those who did not in terms of demographic and clinicopathological parameters. In the BRCA1/2 mutation carrier group, the Ki-67 index and the number of relatives with cancer were higher than the BRCA1/2 non-carrier group. Logistic regression analysis revealed that when the number of relatives with breast or ovarian cancer was ≥2, the risk of carrying the BRCA1/2 mutation increased by 15-fold. Regardless of the type of cancer (including cancers in other organs besides breast or ovary), the risk of carrying the BRCA1/2 mutation increased 1.3 times with each increase in the number of relatives with cancer for the patient with TNBC., Conclusion: In cases with a diagnosis of TNBC, a significant relationship exists between the number of relatives with cancer in the family history and the risk of carrying mutations in the BRCA1/2 genes. This relationship can be confirmed further by large-scale studies with more cases., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (©Copyright 2021 by Turkish Federation of Breast Diseases Associations.)

BRCA1/2 genes with high-penetrance are tumor suppressor and tumor susceptibility genes that play important roles in the homologous recombination mechanism in DNA repair and increase breast cancer risk. Variants in BRCA1 or BRCA2 are the main causes of familial and early-onset breast cancer. This study investigated pathogenic variant belonging to the BRCA2 gene splice region in monozygotic triplets. A 44-year-old woman was diagnosed with breast cancer when she was 32 years old. Her monozygotic sister had a history of breast cancer. No malignancy was detected in the third one of the monozygotic triplets. Sanger sequencing was used to evaluate the BRCA1/2 gene status of the patient and family members. It was figured out that they had the same genetic variant, a heterozygous germ-line splice region variant (c.7008-1G > C) in the BRCA2 gene. This novel splice region variant may be a new pathogenic variant of the BRCA2 gene. Its association with breast cancers needs to be further verified in more patient cases., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)