Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis.

Spinal muscular atrophy (SMA) is a rare, recessively inherited neurodegenerative disorder caused by the presence of pathogenic variants in the SMN gene. As it is the leading inherited cause of infant mortality, identification of SMN gene pathogenic variant carriers is important for diagnostic purposes with effective genetic counseling. Multiple ligation probe analysis (MLPA), a probe-based method, is considered as the gold standard for SMA carrier analysis. However, MLPA might give false-negative results in cases with variations in the probe-binding regions. Here, we present a case born to consanguineous SMA carrier parents. Prenatal diagnosis with MLPA failed to detect the compound heterozygous mutant state of the proband and she was born unfortunately with SMA phenotype. Further analysis with a real-time polymerase chain reaction kit was able to detect the compound heterozygous state of the patient and was confirmed with targeted next-generation sequencing technology.

A Multicenter Study of Genotype Variation/Demographic Patterns in 2475 Individuals Including 1444 Cases With Breast Cancer in Turkey.

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.

An Endocrinological Perspective on 22q11.2 Deletion Syndrome: A Single-center Experience

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.

PGT for structural chromosomal rearrangements in 300 couples reveals specific risk factors but an interchromosomal effect is unlikely.

RESEARCH QUESTION: What factors affect the proportion of chromosomally balanced embryos in structural rearrangement carriers? Is there any evidence for an interchromosomal effect (ICE)? DESIGN: Preimplantation genetic testing outcomes of 300 couples (198 reciprocal, 60 Robertsonian, 31 inversion and 11 complex structural rearrangement carriers) were assessed retrospectively. Blastocysts were analysed either by array-comparative genomic hybridization or next-generation sequencing techniques. ICE was investigated using a matched control group and sophisticated statistical measurement of effect size (φ). RESULTS: 300 couples underwent 443 cycles; 1835 embryos were analysed and 23.8% were diagnosed as both normal/balanced and euploid. The overall cumulative clinical pregnancy and live birth rates were 69.5% and 55.8%, respectively. Complex translocations and female age (≥35) were found to be risk factors associated with lower chance of having a transferable embryo (P < 0.001). Based on analysis of 5237 embryos, the cumulative de-novo aneuploidy rate was lower in carriers compared to controls (45.6% versus 53.4%, P < 0.001) but this was a 'negligible' association (φ < 0.1). A further assessment of 117,033 chromosomal pairs revealed a higher individual chromosome error rate in embryos of carriers compared to controls (5.3% versus 4.9%), which was also a 'negligible' association (φ < 0.1), despite a P-value of 0.007. CONCLUSIONS: These findings suggest that rearrangement type, female age and sex of the carrier have significant impacts on the proportion of transferable embryos. Careful examination of structural rearrangement carriers and controls indicated little or no evidence for an ICE. This study helps to provide a statistical model for investigating ICE and an improved personalized reproductive genetics assessment for structural rearrangement carriers.

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.

Characterization of a Novel Frameshift Mutation Within the TRPS1 Gene Causing Trichorhinophalangeal Syndrome Type 1 in a Kindred Cypriot Family.

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.

Analysis of ACE2 and TMPRSS2 coding variants as a risk factor for SARS-CoV-2 from 946 whole-exome sequencing data in the Turkish population.

Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.

The expression profile of WNT/ß-catanin signalling genes in human oocytes obtained from polycystic ovarian syndrome (PCOS) patients.

Polycystic 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/ß-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/ß-catenin signalling pathway genes (AXIN2, FZD4, TCF4, WNT3, WNT4, WNT5A, WNT7A, WNT1, APC, GSK3B and ß-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 ß-catenin expression levels were similar in the oocytes of both patients and controls, conversely, WNT1 and GSK3ß genes both showed elevated expression in the oocytes of patients with PCOS, therefore suggesting an association between aberrant expression of WNT1 and GSK3ß 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.

Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility.

Background: 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 (M1AP) in the literature, M1AP is known to be crucial for spermatogenesis. Recently, seven variants (five missense, one frameshift, one splice-site) have been reported in the M1AP gene as associated with NOA, cryptozoospermia and oligozoospermia in two separate studies. However, all missense variants were evaluated as variant of uncertain significance by these studies. Therefore, we aimed to analyze their structural impacts on the M1AP protein that could lead to NOA. Methods: 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. Results: 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. Conclusions: 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.

Birt-Hogg-Dubé Syndrome: Diagnostic Journey of Three Cases from Skin to Gene.

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.

Consistency of variant interpretations among bioinformaticians and clinical geneticists in hereditary cancer panels.

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.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

BRCA Variations Risk Assessment in Breast Cancers Using Different Artificial Intelligence Models.

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.

Psychomotor Delay in a Child with FGFR3 G380R Pathogenic Mutation Causing Achondroplasia.

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.

Natural selection at work? Vitamin D deficiency rates and rising health problems in young Turkish Cypriot professionals.

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.

Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells.

Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-α and ER-ß subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-ß in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-ß in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-α did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-ß in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-ß can be successfully targeted by the selective ER-ß agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.

The Importance of Multiple Gene Analysis for Diagnosis and Differential Diagnosis in Charcot Marie Tooth Disease.

AIM: To investigate the genetic etiology of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN). 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 variant. 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.

Functional coding/non-coding variants in EGFR, ROS1 and ALK genes and their role in liquid biopsy as a personalized therapy.

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.

RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells.

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.

Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome.

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.