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The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region
(Galenos Yayincilik, 2021) Yalcintepe, Sinem; Comlek, Fatma Ozguc; Gurkan, Hakan; Demir, Selma; Atli, Emine Ikbal; Atli, Engin; Eker, Damla
Objective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.
Cardiofaciocutaneous Syndrome Phenotype in a Case with de novo KRAS Pathogenic Variant
(Karger, 2020) Sanri, Aslihan; Gurkan, Hakan; Demir, Selma
Cardiofaciocutaneous (CFC) syndrome is one of the developmental disorders caused by a dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway. RASopathies share overlapping clinical features, making the diagnosis challenging, especially in the newborn period. The majority of CFC syndrome cases arise by a mutation in the BRAF, MAP2K1, MAP2K2, or (rarely) KRAS genes. Germline KRAS mutations are identified in a minority of CFC and Noonan syndrome cases. Here, we describe a patient with a KRAS mutation presenting with a CFC syndrome phenotype. The female patient was referred for genetic testing because of congenital exophthalmos. Her facial appearance is distinctive with a coarse face, exophthalmos, ptosis, downslanting palpebral fissures, hypertelorism, deep philtrum, downturned corners of the mouth, and a short neck. She suffered from feeding difficulties, poor weight gain, and developmental delay. The sequencing of the genes involved in the MAPK pathway (PTPN11, SOS1, RAF1, KRAS, NRAS, MAP2K1, SHOC2, CBL, and SPRED1) identified a heterozygous de novo NM_004985.4:c.173C>T (p.Thr58Ile) in the KRAS gene. Germline KRAS mutations have been identified in approximately 2% of the reported NS cases and less than 5% of the reported CFC syndrome cases. Because CFC and Noonan syndrome share clinical overlapping features, the phenotype caused by KRAS mutations is often difficult to assign to one of the 2 entities. The mutation that we detected in our patient was previously reported in a patient with an Noonan syndrome phenotype. However, our patient predominantly exhibits CFC clinical features. In our case, coarse facial appearance and severe developmental delay help discriminate CFC from Noonan syndrome. Thus, patient follow-up, especially for delayed motor milestones suspected from RASopathies, is important for the discrimination of overlapping conditions as in the abovementioned syndromes.
A Child with 5q Deletion and Accompanying Chiari 1 Malformation
(Springer India, 2020) Atli, Emine Ikbal; Yalcintepe, Sinem; Atli, Engin; Demir, Selma; Gurkan, Hakan
[Abstract Not Available]
Clinical exome sequencing reveals an important role for clinical diagnosis of intellectual disability with definition of seven novel variants
(Asean Neurological Assoc, 2023) Yalcintepe, Sinem; Gorker, Isik; Bozatli, Leyla; Guler, Hazal Sezginer; Zhuri, Drenushe; Demir, Selma; Atli, Emine Ikbal
Intellectual disability can be defined as a significantly below-average general mental function, accompanied by environmental adaptation and behavioural deterioration. Patient files of 87 children with intellectual disability were evaluated in this study. After clinical exclusion criterias, clinical exome sequencing was performed for 25 of 87 intellectual disability cases with a massively parallel targeted sequencing method. Seventeen variants in the genes MBOAT7, KDM5C, TUBB3, MAN1B1, GFAP, CACNA1A, BCOR, LMNA, LBR, ALS2, ENPP1, UBE3A, TRAPPC9, HSPG2, AFF2, NLGN4, and SOX10 were identified in 14 of 25 patients (56%). Seven of the 17 variants (41.1%) were novel in the genes KDM5C, BCOR, UBE3A, TRAPPC9, AFF2, NLGN4, and SOX10. Seven cases (7/25, 28%) had a definite diagnosis of intellectual disability with their pathogenic variants. The high rate of variant detection (56%) in the current study shows that multiple gene analysis plays an essential role in diagnosing the uncertain etiology of intellectual disability. This study also presents seven novel variants, which are first reported.
Clinical Implications of Chromosome 16 Copy Number Variation
(Karger, 2022) Atli, Emine Ikbal; Yalcintepe, Sinem; Atli, Engin; Demir, Selma; Mail, Cisem; Gurkan, Hakan
Chromosome 16 is one of the gene-rich chromosomes; however, approximately 10% of the chromosome 16 sequence is composed of segmental copies, which renders this chromosome instable and predisposes it to rearrangements via frequent nonallelic homologous recombination. Microarray technologies have enabled the analysis of copy number variations (CNV), which may be associated with the risk of developing complex diseases. Through comparative genomic hybridisation in 1,298 patients, we detected 18 cases with chromosome 16 CNV. We identified 2recurrent CNV regions, including 1 at 16p13.11 in 4 patients and another at 16p11.2 in 7 patients. We also detected atypical chromosome 16 rearrangements in 7 patients. Furthermore, we noted an increased frequency of co-occurring genomic changes, supporting the two-hit hypothesis to explain the phenotypic variability in the clinical presentation of CNV syndromes. Our findings can contribute to the creation of a chromosome 16 disease map based on regions that may be associated with disease development.
Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic KRAS Variation
(Karger, 2022) Demir, Selma; Kostek, Huemeyra Yasar; Sanri, Aslihan; Yildirim, Ruken; Comlek, Fatma Oezguec; Yalcintepe, Sinem; Deveci, Murat
Introduction: Germline pathogenic variations of the genes encoding the components of the Ras-MAPK pathway are found to be responsible for RASopathies, a clinically and genetically heterogeneous group of diseases. In this study, we aimed to present the results of patients genetically investigated for RASopathy-related mutations in our Genetic Diagnosis Center. Methods: The results of 51 unrelated probands with RASopathy and 4 affected relatives (31 male, 24 female; mean age: 9.327 +/- 8.214) were included in this study. Mutation screening was performed on DNA samples from peripheral blood of the patients either by Sanger sequencing of PTPN11 hotspot regions (10/51 probands), or by a targeted amplicon next-generation sequencing panel (41/51 probands) covering the exonic regions of BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RASA2, RIT1, SHOC2, SOS1, SOS2, SPRED1, and KAT6B genes. Results: Pathogenic/likely pathogenic variations found in 22 out of 51 probands (43.13%) and their 4 affected family members were located in PTPN11, BRAF, KRAS, NF1, RAF1, SOS1, and SHOC2 genes. The c.148A>C (p.Thr50Pro) variation in the KRAS gene was a novel variant detected in a sibling in our patient cohort. We found supportive evidence for the pathogenicity of the NF1 gene c.5606G>T (p.Gly1869Val) variation which we defined in an affected boy who inherited the mutation from his affected father. Conclusion: Although PTPN11 is the most frequently mutated gene in our patient cohort, as in most previous reports, different mutation distribution among the other genes studied motivates the use of a next-generation sequencing gene panel including the possible responsible genes.
Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants
(Galenos Publ House, 2021) Demir, Selma; Yalcintepe, Sinem; Atli, Engin; Yalcin, Yelda; Atli, Emine Ikbal; Eker, Damla; Karal, Yasemin
Background: Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex. Aims: To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex. Study design: Retrospective, cross-sectional study. Methods: Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines. Results: In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene. Conclusion: The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.
The Correlation of Cystic Fibrosis Screening Test Results with Ultrasonographically Detected Fetal Anomalies in Prenatal Diagnosis
(Galenos Publ House, 2023) Atli, Emine Ikbal; Atli, Engin; Demir, Selma; Yalcintepe, Sinem; Gurkan, Hakan
Objective: In a multiethnic community, our goal was to assess the applicability of this method. Here we offer a collection of 112 diagnostic prenatal samples for which a comprehensive study of exons, exons/intron boundaries, and major rearrangements has been investigated in prenatal samples of fetuses with suspected cystic fibrosis over the past decade.Methods: For the CFTR mutation study, 112 prenatal samples (amniotic fluid, chorionic villi, or cultured cells from amniotic fluid or chorionic villi) were brought into our lab. QIAseq Targeted NGS DNA Panel (Qiagen, Hilden, Germany) was performed to analyze the CFTR gene (27 exons).Results: The pathogenic variation NM000492.4(CFTR):c.3454G>C was the most often found (p.Asp1152His), which accounted for 50% of the classic pathogenic CF variants in the study population. Compound heterozygous CFTR pathogenic variations were detected in one of our patients. NM000492.3(CFTR):c.2620-15C>G and NM000492.3(CFTR):c.2756A>G Two variants, one of which was reported as VUS and the other as pathogenic, were detected in a 17-week -old fetus (0.89%). Fetus inherited the NM000492.3(CFTR):c.2756A>G variant from mother and the NM000492.3(CFTR):c.2620-15C>G variant from father. There is an isolated hyperechoic bowel sign at 17 weeks of pregnancy.Conclusion: In our case series, genetic analyzes suggest that an affected child may be heterozygous for CFTR mutations, compound heterozygous for two clinically significant recessive mutations inherited from healthy carrier parents. Early prenatal genetic testing pretesting and posttesting genetic counseling is crucial in the management of future pregnancies in heterozygous couples which are healthy carriers for CFTR mutations.
Customised targeted massively parallel sequencing enables more precisely diagnosis of patients with epilepsy
(Wiley, 2022) Atli, Emine Ikbal; Atli, Engin; Yalcintepe, Sinem; Demir, Selma; Kalkan, Rasime; Eker, Damla; Gurkan, Hakan
Background Advancement in genetic technology has led to the identification of an increasing number of genes in epilepsy. This will provide a lot of information in clinical practice and improve the diagnosis and treatment of epilepsy. Aim To show the importance of genes in the next-generation sequencing (NGS) panel during the evaluation of epilepsy and to emphasise the importance of genetic studies in different populations for the evaluation of genes that cause disease. Methods This was a single-centre retrospective cohort study of 80 patients who underwent NGS testing with a customised epilepsy panel. Results In a total of 54 (67.5%) out of 80 patients, pathogenic or likely pathogenic variants and variants of uncertain significance (VOUS) were identified according to the American College of Medical Genetics and Genomics criteria. Pathogenic or likely pathogenic variants (n = 35) were identified in 29 (36.25%) out of 80 individuals. VOUS (n = 34) were identified in 28 (35%) out of 80 patients. Pathogenic, likely pathogenic and VOUS were most frequently identified in TSC2 (n = 11), SCN1A (n = 6) and TSC1 (n = 5) genes. Other common genes were KCNQ2 (n = 3), AMT (n = 3), CACNA1H (n = 3), CLCN2 (n = 3), MECP2 (n = 2), ASAH1 (n = 2) and SLC2A1 (n = 2). Conclusions NGS-based testing panels contribute to the diagnosis of epilepsy and might change the clinical management by preventing unnecessary and potentially harmful diagnostic procedures and management in patients. Thus, our results highlight the benefit of genetic testing in children suffering with epilepsy.
Distal 3p Duplication and 22q13.3 Deletion with Severe Hypotonia Originating from a Paternal Balanced Translocation (3;22)
(Karger, 2020) Yalcintepe, Sinem; Atli, Emine I.; Atli, Engin; Demir, Selma; Ciftdemir, Nukhet A.; Duran, Ridvan; Ozdemir, Janset
In this study, we present a case with distal 3p duplication and 22q13.3 deletion due to unbalanced meiotic segregation in her father carrying a balanced translocation. The 2-month-old girl was examined for her severe hypotonia, developmental delay, and mild dysmorphic appearance. Clinical features include broad forehead, hypertelorism, laterally extended eyebrows, long eyelashes, a depressed nasal root, bifid nasal tip, long philtrum, thin lips, posteriorly rotated ears, short neck, partial syndactyly of the right hand (fingers 3, 4) , and partial syndactyly of the right foot (toes 2, 3). After examination, the final karyotype was reported as: 46,XX,der(22)del(22)(qter)dup(3)(p22pter), and the array-CGH results showed arr[GRCh37] 3p26.3p22.1(93949_41518607)x3 and arr[GRCh37] 22q13.31q13.33(44554083_51224252)x1. The mother has a 46,XX karyotype, and her father carries a balanced translocation, 46,XY,t(3;22)(p26.3;q13.3). This is the first case with a distal 3p duplication and 22q13.3 deletion with severe hypotonia and developmental delay.
Does Gender Difference Effect Radiation-Induced Lung Toxicity? An Experimental Study by Genetic and Histopathological Predictors
(Radiation Research Soc, 2022) Cosar, Rusen; Ozen, Alaattin; Tastekin, Ebru; Sut, Necdet; Cakina, Suat; Demir, Selma; Parlar, Sule
Several studies have reported differences in radiation toxicity between the sexes, but these differences have not been tested with respect to histopathology and genes. This animal study aimed to show an association between histopathological findings of radiation-induced lung toxicity and the genes ATM, SOD2, TGF-beta 1, XRCC1, XRCC3 and HHR2. In all, 120 animals were randomly divided into 2 control groups (male and female) and experimental groups comprising fifteen rats stratified by sex, radiotherapy (0 Gy vs. 10 Gy), and time to sacrifice (6, 12, and 24 weeks postirradiation). Histopathological evaluations for lung injury, namely, intra-alveolar edema, alveolar neutrophils, intra-alveolar erythrocytes, activated macrophages, intra-alveolar fibrosis, hyaline arteriosclerosis, and collapse were performed under a light microscope using a grid system; the evaluations were semi quantitatively scored. Then, the alveolar wall thickness was measured. Real-time quantitative reverse transcription PCR (RT-qPCR) was used to determine gene expression differences in ATM, TGF-beta 1, XRCC1, XRCC3, SOD2 and HHR2L among the groups. Histopathological data showed that radiation-induced acute, subacute, and chronic lung toxicity were worse in male rats. The expression levels of the evaluated genes were significantly higher in females than males in the control group, but this difference was lost over time after radiotherapy. Less toxicity in females may be attributable to the fact that the expression of the evaluated genes was higher in normal lung tissue in females than in males and the changes in gene expression patterns in the postradiotherapy period played a protective role in females. Additional data related to pulmonary function, lung weights, imaging, or outcomes are needed to support this data that is based on histopathology alone. (C) 2022 by Radiation Research Society
Effective Use of Next Generation Sequencing For Genetic Diagnosis of a Patient With a Mosaic Tsc2 Variant
(Trakya Üniversitesi, 2018) Çifcibaşı, Hilal Sena; Gülbal, Elçin; Erdoğan, Ayşenur; Demirci, Ayşenur; Demir, Selma
Aims: Tuberous sclerosis complex is a genetic disorder characterized by mutations in Tuberous Sclerosis Complex 1 (* 605284) or Tuberous Sclerosis Complex 2 (* 191092) genes. PALB2 (* 610355) gene has long been known to be associated with increased breast and pancreatic cancer risk. Its association with risk of stomach and lung cancers has also been established recently. In this case report, it is aimed to present a case of a 24-year-old female patient, who has been diagnosed with both novel mosaic Tuberous Sclerosis Complex 2 pathogenic variation and pathogenic PALB2 variation at the same time. Case Report: A 24-year-old female patient was admitted to Trakya University Genetic Diseases Center with suspected tuberous sclerosis complex. Her primary complaints were a continuous headache and fatigue. She had no history of convulsion and seizure. There were bilateral facial angiofibromas around her nose. When genomic DNA was isolated, both novel mosaic Tuberous Sclerosis Complex 2 pathogenic variation and pathogenic PALB2 variation were observed. Conclusion: This case report shows that in cancer predisposing syndromes, Next-generation sequencing is a powerful technique to portrait a detailed genetic profile of patient, investigating for any mosaicism or other risk alleles
THE EFFECTIVENESS OF PTPN11 GENE ANALYSIS IN THE PRENATAL DIAGNOSIS OF NOONAN SYNDROME
(Istanbul Univ, Fac Medicine, Publ Off, 2021) Toksoy, Guven; Tepgec, Fatih; Sarac Sivrikoz, Tugba; Kalelioglu, Ibrahim Halil; Demir, Selma; Has, Recep; Yuksel, Atil
Objective: Dominant pathogenic variants in 29 RAS-MAPK (Rat-sarcoma-Mitogen-activated-protein-kinase) pathway genes, important for the regulation of cell growth, differentiation, aging and cell-cycle, are responsible for RASopathies, Noonan syndrome (NS) is the most common form. PTPN11 variants are detected in 50% of the cases, 90% being identified in the first SH2 and in the catalytic domain at the N- and C-terminals of the peptide, respectively. Increased nuchal translucency (NT), lymphatic system anomalies (cystic hygroma, pleural effusion, ascites), cardiac anomalies, polyhydramnios, short limb and macrocephaly are the NS-associated prenatal findings. PTPN11 association is reported in 2-3% of normal karyotyped fetuses with NT and in >10% when other NS findings are included. Material and Method: PTPN11 analysis with different approaches in 246 normal karyotyped prenatal cases with NS-associated USG findings were retrospectively evaluated. The targeted PTPN11 regions in 200 and the whole gene structure of 46 cases were examined by Sanger sequencing. Results: Pathogenic variants, including two novel variants (p.P107S and p.M504T), were identified in two fetuses with isolated NT and in three fetuses with multiple USG findings, leading to a 2% of detection rate, all found in targeted exons. Two of six cases, further investigated for targets of four Rasopathy genes, had causative genes in SOS1. One of three terminated fetuses, investigated for the targeted-gene panel, had a causative gene in RAF1 genes. Both the isolated NT and multiple USG finding groups revealed an equal detection rate of 2.3%. Discussion: PTPN11 is responsible for 50% of RASopathies and 90% of the pathogenic variants are delineated in the targeted exons. The rational, cost-effective approach for the clarification of the genetic basis of RASopathies is screening the addressed exons of PTPN11 followed by the other exons and other RASopathy related genes.
First Report of Jacobsen Syndrome with Dextrocardia Diagnosed with del(11)(q24q25)
(Karger, 2022) Yalcintepe, Sinem; Zhuri, Drenushe; Sezginer Guler, Hazal; Atli, Engin; Demir, Selma; Atli, Emine Ikbal; Mail, Cisem
Jacobsen syndrome is a rare congenital disorder that is caused by the deletion of several genes in chromosome 11. A 10-year-old female with congenital heart disease, dextrocardia, and coarse facial appearance was examined in our medical genetics clinic. Chromosome analysis and array-CGH showed a copy number loss of 9 Mb in the 11q24.2q25 region. Herein, we report her clinical findings. This is the first case of Jacobsen syndrome with dextrocardia.
The Frequency of SMN1, SMN2 Copy Numbers in 246 Turkish Cases Analyzed with MLPA Method
(Thieme Medical Publ Inc, 2023) Yalcintepe, Sinem; Karal, Yasemin; Demir, Selma; Atli, Emine Ikbal; Atli, Engin; Eker, Damla; Mail, Cisem
This study aimed to define the copy numbers of SMN1 and SMN2 genes and the diagnosis rate and carrier frequency of spinal muscular atrophy (SMA) in the Thrace region of Turkey. In this study, the frequency of deletions in exons 7 and 8 in the SMN1 gene and SMN2 copy numbers were investigated. A total of 133 cases with the preliminary diagnosis of SMA and 113 cases with the suspicion of being an SMA carrier from independent families were analyzed by multiplex ligation-dependent probe amplification method for SMN1 and SMN2 gene copy numbers.SMN1 homozygous deletions were detected in 34 patients (25.5%) of 133 cases with the suspicion of SMA. Cases diagnosed with SMA type I was 41.17% (14/34), 29.4% (10/34) with type II, 26.4% (9/34) with type III, and 2.94% (1/34) with type IV. The SMA carrier rate was 46.01% in 113 cases. In 34 SMA cases, SMN2 copy numbers were: two copies - 28 cases (82.3%), three copies - 6 cases (17.6%). SMN2 homozygous deletions were detected in 15% (17/113) of carrier analysis cases. The consanguinity rate of the parents was 23.5% in SMA diagnosed cases. In this study, we had a 25.5% of SMA diagnosis rate and 46% SMA carrier frequency. The current study also showed the relatively low consanguinity rate of the Thrace region, with 23.5% according to the east of Turkey.
Genetic Diagnosis of Hereditary Hemorrhagic Telangiectasia: Four Novel Pathogenic Variations in Turkish Patients
(2020) Baysal, Mehmet; Demir, Selma; Ümit, Elif G.; Gürkan, Hakan; Baş, Volkan; Gülarslan, Sedanur Karaman; Demir, Ahmet Muzaffer
Aims: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by telangiectasia, epistaxis, and vascular malformations. Pathogenic mutations were found in ENG, AVCRL1, SMAD4, and GDF genes. In this study, we present our database of patients with hereditary hemorrhagic telangiectasia regarding the phenotype-genotype relations and discuss two novel ENG gene pathogenic variations in two unrelated families. Methods: Next Generation Sequencing analysis was performed on the peripheral blood of nine patients with hereditary hemorrhagic telangiectasia in four unrelated families. All patients were diagnosed with hereditary hemorrhagic telangiectasia according to the Curaçao criteria. Data on treatment and screenings of visceral involvement were recorded from files. Results: We have found a pathogenic variation in either the ENG or ACVRL1 gene in each family. Two novel pathogenic variations in the ENG gene, including NM_000118.3 (ENG): c.416delC (p.P139fs*24) and NM_000118.3(ENG): c.1139dupT (p.Leu380PhefsTer16), were found in the same family. The NM_000020.2(ACVRL1): c.1298C>T (p.Pro433Leu) pathogenic variation in the ACVRL1 gene in our first family and a novel heterozygous likely pathogenic NM_000020.2(ACVRL1): c.95T>C (p.Val32Ala) variation was found in our second family. Seven of the nine patients were treated with thalidomide for controlling bleeding episodes. All patients responded to thalidomide. In one patient, the response to thalidomide was lost and switched to bevacizumab. Conclusion: In hereditary hemorrhagic telangiectasia, certain types of mutations correlate with disease phenotypes and with next generation sequencing methods. New pathogenic variations can be revealed, which might help manage patients with hereditary hemorrhagic telangiectasia
Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey
(Imprimatur Publications, 2020) Demir, Selma; Tozkir, Hilmi; Gurkan, Hakan; Atli, E. Ikbal; Yalcintepe, Sinem; Atli, Engin; Sezer, Y. Atakan
Purpose: Pathogenic/likely pathogenic (P/LP) germline variations in BRCA1 and BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. This study presents the BRCA1/BRCA2 sequencing and deletion duplication analyses results of of 493 participants (485 women, 8 men) selected based on the National Comprehensive Cancer Network (NCCN) guidelines. Methods: Next generation sequencing (NGS) and multiplex ligation-dependent probe amplification methods (MLPA) were used to define germline BRCA1/BRCA2 positivity. Results: Overall, the P/LP frequency of the participants was 17.8%. Five of the likely pathogenic variants were novel. The 5266dupC pathogenic variation, which is a founder mutation in the Ashkenazi Jewish population, was the most common variation among the patients, with a frequency of 5.47%. The pathogenic/likely pathogenic variation frequency was significantly higher (p=0.01) among clinically diagnosed familial cancer patisents than those participants without personal history of cancer but enrolled for BRCA1 testing due to familial risk. BRCA1/BRCA mutation positivity was significantly higher (p=0.000) among those who had at least one first- or second-degree relative with breast/ovarian cancer from patients who had no family history. BRCA1/BRCA2 mutation positivity was 69.23% between the patients who had personal history of both breast and ovarian cancer. Conclusion: Based on our findings, we suggest that sequencing all of the coding regions of the BRCA1/BRCA2 genes using NGS is a feasible approach for individuals who are at risk of developing BRCA-related cancer according to NCCN guidelines. The 5266dupC pathogenic variation, as the most common pathogenic variation in the Trakya region of Turkey, should be included if a targeted mutatin screening is planned.
Genotype-phenotype correlations of pathogenic copy number variations on X chromosome detected by comparative genomic hybridization
(Elsevier, 2022) Yalcintepe, Sinem; Atli, Engin; Atli, Emine Ikbal; Demir, Selma; Ozen, Yasemin; Mail, Cisem; Gurkan, Hakan
The aim of this study was to present genotype-phenotype correlations of pathogenic copy number variations (CNVs) on X chromosome. Clinical and microarray data of the cases were collected. Conventional cytogenetics and CytoSure 4x180K oligonucleotide array (Agilent Technologies, Inc.) (Comparative Genomic Hybridization - CGH) was applicated to all cases. Molecular and clinical characterisation of these CNVs was performed in this study. 18 cases were included in this study for having a pathogenic CNV on X chromosome. The changes were reported pathologically by evaluating break points, anomaly size, number of involved genes and their functions and phenotypic correlations. 16 cases with pathogenic CNVs of X chromosome were examined with the clinical findings of multiple congenital anomalies, mental retardation, eosophageal atresia, duodenal atresia, autism spectrum disorder, hypogonadotropic hypogonadism, dysmorphic features, muscular dystrophy, hydrocephaly, neuromotor growth retardation, trigonocephaly, high risk of prenatal screening test, recurrent pregnancy loss with reciprocal translocation, fetal loss with multiple congenital anomalies. 2 cases were diagnosed as Turner Syndrome with rare karyotypes and array-CGH results. Our study contributes to the genotype/phenotype correlation with the delineation of laboratory criteria which help to classify the different CNVs detected on X chromosome. Atypical microdeletions/duplications allowed us to define minimal critical regions that could be responsible for specific clinical findings of the syndromes and to highlight some genes.
Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma
(Codon Publications, 2021) Yalcintepe, Sinem; Gurkan, Hakan; Korkmaz, Fatma Nur; Demir, Selma; Atli, Engin; Eker, Damla; Guler, Hazal Sezginer
The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B. RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.
Homozygous Val6Gly Variation in PRDM5 Gene Causing Brittle Cornea Syndrome: A New Turkish Case
(Karger, 2023) Sanri, Aslihan; Demir, Selma; Gurkan, Hakan
Introduction: Brittle cornea syndrome (BCS) is a rare connective tissue disorder with ocular and systemic features. Extreme corneal thinning and fragility are the main hallmarks of BCS. Case Report: A 4-year-old boy presented with recurrent spontaneous corneal perforation. He had blue sclera, corneal leucoma, irregular iris, shallow anterior chamber, corneal astigmatism, and bilateral corneal thinning. He also had several systemic features including hearing loss, skin hyperelasticity, joint hypermobility, scoliosis, and umbilical hernia. A diagnosis of BCS was confirmed with molecular analysis. A homozygous c.17T>G, p.(Val6Gly) variation was identified in the PRDM5 gene. Discussion: p.(Val6Gly) variation in PRDM5 was previously reported in 2 patients with BCS. We also considered PRDM5 c.17T>G, p.(Val6Gly) variation as pathogenic based on the following features: the absence of the variation in population databases, in silico predictions, segregation analysis, and clinical signs of our patient. Extremely thin and brittle corneas lead to corneal perforation spontaneously or after minor trauma. Nearly all patients have lost their vision because of corneal rupture and scars. The key challenge in the management of BCS is the prevention of ocular rupture which relies on early diagnosis. Early diagnosis allows for taking prompt measures to prevent ocular rupture.

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