Awol Mekonnen Ali, Haileyesus Adam, Daniel Hailu, Rawleigh Howe, Teferra Abula, Marieke J H Coenen
Introduction: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1, and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function.
Objective: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia.
Methods: Three variants GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in PNPLA3 (rs738409) was genotyped to assess the association with liver function.
Results: Genotype frequencies of GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between PNPLA3 rs738409 and liver function could not be investigated due to a lack of clinical information.
Conclusion: In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.
l -天冬酰胺酶是治疗儿童急性淋巴细胞白血病(ALL)的重要成分;然而,超敏反应和肝毒性阻碍了其抗肿瘤作用。先前的报道表明,CNOT3、GRIA1和NFATC2基因的遗传变异可能与超敏反应有关,PNPLA3与肝功能有关。目的:在本研究中,研究了这种关联是否也存在于来自埃塞俄比亚的儿科ALL队列中。方法:对160例患者的3种变异GRIA1 rs4958351、CNOT3 rs73062673和NFATC2 rs6021191进行基因分型。采用logistic回归分析进行关联分析,以调查与超敏反应的关系。除了这些变异外,PNPLA3的一个变异(rs738409)被基因分型以评估其与肝功能的关系。结果:GRIA1 rs4958351、CNOT3 rs73062673、NFATC2 rs6021191基因型频率均高于/低于文献报道。144例患者纳入关联分析,其中18例(12.5%)发生L-ASP超敏反应。虽然携带上述三种基因风险等位基因的患者出现超敏反应的频率较高,但差异无统计学意义。由于缺乏临床资料,无法对PNPLA3 rs738409与肝功能的相关性进行分析。结论:总而言之,所有检测的基因都不能预测埃塞俄比亚儿科ALL患者的l -天冬酰胺酶过敏。
{"title":"Evaluating the Frequencies of <i>CNOT3, GRIA1, NFATC2</i>, and <i>PNPLA3</i> Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia.","authors":"Awol Mekonnen Ali, Haileyesus Adam, Daniel Hailu, Rawleigh Howe, Teferra Abula, Marieke J H Coenen","doi":"10.2147/TACG.S404695","DOIUrl":"https://doi.org/10.2147/TACG.S404695","url":null,"abstract":"<p><strong>Introduction: </strong>L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in <i>CNOT3, GRIA1</i>, and <i>NFATC2</i> genes might be associated with hypersensitivity reactions and <i>PNPLA3</i> with liver function.</p><p><strong>Objective: </strong>In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia.</p><p><strong>Methods: </strong>Three variants <i>GRIA1</i> rs4958351, <i>CNOT3</i> rs73062673, and <i>NFATC2</i> rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in <i>PNPLA3</i> (rs738409) was genotyped to assess the association with liver function.</p><p><strong>Results: </strong>Genotype frequencies of <i>GRIA1</i> rs4958351, <i>CNOT3</i> rs73062673, and <i>NFATC2</i> rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between <i>PNPLA3</i> rs738409 and liver function could not be investigated due to a lack of clinical information.</p><p><strong>Conclusion: </strong>In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ae/a9/tacg-16-131.PMC10404408.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9956830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Son The Trinh, Nhat Ngoc Nguyen, Hien Thi Thu Le, Hanh Thi My Pham, Sang Tien Trieu, Ngoc Thao My Tran, Hung Sy Ho, Danh Van Tran, Tam Van Trinh, Hiep Trong Hoang Nguyen, Ngoc Pham Minh, Trinh Duc Dang, Viet Huu Dinh, Hang Thi Doan
Background: The Y chromosome has a specific region, namely the Azoospermia Factor (AZF) because azoospermia is typically reported in the microdeletion of the AZF region. This study aims to assess the characteristics of AZF microdeletion after screening a massive number of low sperm concentration men; and the Microdissection testicular sperm extraction (mTESE) outcomes for retrieving sperm from azoospermic patients.
Materials and methods: This retrospective multiple-center study enrolled a total of 1121 men with azoospermia, cryptozoospermia, and severe oligozoospermia from December 2016 to June 2022. An extension analysis used a total of 17 STSs to detect the position-occurring microdeletion in the AZF region (AZFa, b, c, and/or d loci). Microdissection testicular sperm extraction (mTESE) was performed to retrieve sperm in azoospermic men diagnosed AZFc microdeletion.
Results: One hundred and fifty-three men carried AZF microdeletion were detected in the 1121 participants (13.64%). The incidences of AZF microdeletion were confined to AZF a, c, and d regions, both individual and concurrence, with the most common in the AZFc region accounting for 49.67%; There was no significant difference in clinical and paraclinical characteristics between the deleted regions, except FSH level (highest in AZFa microdeletion, p = 0.043). The AZFc region was the most common type of AZF microdeletion (49.67%), including complete microdeletion (4 patients) and gr/gr partial microdeletion (39 patients) with 50.00% and 63.63% in the success rate of mTESE, separately.
Conclusion: The absence of AZFa and/or AZFb regions often express the most severe phenotype - azoospermia and the increasing FSH level. The AZFc region played the most common microdeletion. Microdissection testicular sperm extraction (mTESE) was the possible therapy for sperm retrieval from the testis of azoospermia men having AZFc microdeletion.
{"title":"Screening Y Chromosome Microdeletion in 1121 Men with Low Sperm Concentration and the Outcomes of Microdissection Testicular Sperm Extraction (mTESE) for Sperm Retrieval from Azoospermic Patients.","authors":"Son The Trinh, Nhat Ngoc Nguyen, Hien Thi Thu Le, Hanh Thi My Pham, Sang Tien Trieu, Ngoc Thao My Tran, Hung Sy Ho, Danh Van Tran, Tam Van Trinh, Hiep Trong Hoang Nguyen, Ngoc Pham Minh, Trinh Duc Dang, Viet Huu Dinh, Hang Thi Doan","doi":"10.2147/TACG.S420030","DOIUrl":"https://doi.org/10.2147/TACG.S420030","url":null,"abstract":"<p><strong>Background: </strong>The Y chromosome has a specific region, namely the Azoospermia Factor (AZF) because azoospermia is typically reported in the microdeletion of the AZF region. This study aims to assess the characteristics of AZF microdeletion after screening a massive number of low sperm concentration men; and the Microdissection testicular sperm extraction (mTESE) outcomes for retrieving sperm from azoospermic patients.</p><p><strong>Materials and methods: </strong>This retrospective multiple-center study enrolled a total of 1121 men with azoospermia, cryptozoospermia, and severe oligozoospermia from December 2016 to June 2022. An extension analysis used a total of 17 STSs to detect the position-occurring microdeletion in the AZF region (AZFa, b, c, and/or d loci). Microdissection testicular sperm extraction (mTESE) was performed to retrieve sperm in azoospermic men diagnosed AZFc microdeletion.</p><p><strong>Results: </strong>One hundred and fifty-three men carried AZF microdeletion were detected in the 1121 participants (13.64%). The incidences of AZF microdeletion were confined to AZF a, c, and d regions, both individual and concurrence, with the most common in the AZFc region accounting for 49.67%; There was no significant difference in clinical and paraclinical characteristics between the deleted regions, except FSH level (highest in AZFa microdeletion, p = 0.043). The AZFc region was the most common type of AZF microdeletion (49.67%), including complete microdeletion (4 patients) and gr/gr partial microdeletion (39 patients) with 50.00% and 63.63% in the success rate of mTESE, separately.</p><p><strong>Conclusion: </strong>The absence of AZFa and/or AZFb regions often express the most severe phenotype - azoospermia and the increasing FSH level. The AZFc region played the most common microdeletion. Microdissection testicular sperm extraction (mTESE) was the possible therapy for sperm retrieval from the testis of azoospermia men having AZFc microdeletion.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a0/88/tacg-16-155.PMC10473397.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10153198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Van K Ma, Rong Mao, Jessica N Toth, Makenzie L Fulmer, Alena S Egense, Suma P Shankar
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.
{"title":"Prader-Willi and Angelman Syndromes: Mechanisms and Management.","authors":"Van K Ma, Rong Mao, Jessica N Toth, Makenzie L Fulmer, Alena S Egense, Suma P Shankar","doi":"10.2147/TACG.S372708","DOIUrl":"https://doi.org/10.2147/TACG.S372708","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/76/51/tacg-16-41.PMC10084876.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karin E M Diderich, Jasmijn E Klapwijk, Vyne van der Schoot, Hennie T Brüggenwirth, Marieke Joosten, Malgorzata I Srebniak
The yield of genetic prenatal diagnosis has been notably improved by introducing whole genome chromosomal microarray (CMA) and prenatal exome sequencing (pES). However, together with increased numbers of diagnoses made, the need to manage challenging findings such as variants of unknown significance (VUS) and incidental findings (IF) also increased. We have summarized the current guidelines and recommendations and we have shown current solutions used in our tertiary center in the Netherlands. We discuss four of the most common clinical situations: fetus with normal pES results, fetus with a pathogenic finding explaining the fetal phenotype, fetus with a variant of uncertain clinical significance fitting the phenotype and fetus with a variant leading to an incidental diagnosis. Additionally, we reflect on solutions in order to facilitate genetic counseling in an NGS-era.
{"title":"Challenges and Pragmatic Solutions in Pre-Test and Post-Test Genetic Counseling for Prenatal Exome Sequencing.","authors":"Karin E M Diderich, Jasmijn E Klapwijk, Vyne van der Schoot, Hennie T Brüggenwirth, Marieke Joosten, Malgorzata I Srebniak","doi":"10.2147/TACG.S411185","DOIUrl":"https://doi.org/10.2147/TACG.S411185","url":null,"abstract":"<p><p>The yield of genetic prenatal diagnosis has been notably improved by introducing whole genome chromosomal microarray (CMA) and prenatal exome sequencing (pES). However, together with increased numbers of diagnoses made, the need to manage challenging findings such as variants of unknown significance (VUS) and incidental findings (IF) also increased. We have summarized the current guidelines and recommendations and we have shown current solutions used in our tertiary center in the Netherlands. We discuss four of the most common clinical situations: fetus with normal pES results, fetus with a pathogenic finding explaining the fetal phenotype, fetus with a variant of uncertain clinical significance fitting the phenotype and fetus with a variant leading to an incidental diagnosis. Additionally, we reflect on solutions in order to facilitate genetic counseling in an NGS-era.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7c/85/tacg-16-89.PMC10198275.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9509641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lisa Ximena Rodriguez-Rojas, Estephania Candelo, Harry Pachajoa, Juan Esteban Garcia-Robledo, Jose Antonio Nastasi-Catanese, Jorge Andres Olave-Rodriguez, Angela R Zambrano
Background: Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on MUTYH mutations are on Caucasian patients.
Material and methods: We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis.
Conclusion: With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.
{"title":"The Unique Spectrum of <i>MUTYH</i> Germline Mutations in Colombian Patients with Extracolonic Carcinomas.","authors":"Lisa Ximena Rodriguez-Rojas, Estephania Candelo, Harry Pachajoa, Juan Esteban Garcia-Robledo, Jose Antonio Nastasi-Catanese, Jorge Andres Olave-Rodriguez, Angela R Zambrano","doi":"10.2147/TACG.S370416","DOIUrl":"https://doi.org/10.2147/TACG.S370416","url":null,"abstract":"<p><strong>Background: </strong>Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with <i>MUTYH</i> mutations is <i>MUTYH</i>-associated polyposis, a form of familial colorectal cancer syndrome. <i>MUTYH</i> may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on <i>MUTYH</i> mutations are on Caucasian patients.</p><p><strong>Material and methods: </strong>We analyzed a small cohort of non-Caucasian, Colombian cancer patients with <i>MUTYH</i> germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without <i>MUTYH</i>-associated polyposis.</p><p><strong>Conclusion: </strong>With this case series, we intended to provide important data for the understanding of <i>MUTYH</i> as a possible driver of familial cancer, even when only heterozygous mutations are found.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5a/2d/tacg-16-53.PMC10122495.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9383856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: BRCA1 and BRCA2 genes represent the most investigated breast and ovarian cancer predisposition genes. Ten cases of pathogenic de novo BRCA1 variations and six cases of pathogenic de novo BRCA2 variation have been reported at present. Here, we report a new case of a de novo BRCA1 gene mutation.
Case presentation: A 30-year-old woman with no health issues and no family history for hereditary breast and ovarian cancer was diagnosed with a hormone receptor positive/HER2 negative invasive breast cancer. Genetic testing revealed a pathogenic variant in BRCA1 (c.4065_4068delTCAA) which was not found in her parents or sister.
Conclusion: We report a new case of de novo BRCA1 mutation, confirmed by repeated germline testing of the index patient and her parents. The published BRCA1/2 de novo mutation rate is low. This is probably due - in part - to the strict testing criteria.
{"title":"A New de novo <i>BRCA1</i> Mutation in a Young Breast Cancer Patient: A Case Report.","authors":"Amina Scherz, Susanna Stoll, Benno Rothlisberger, Manuela Rabaglio","doi":"10.2147/TACG.S405120","DOIUrl":"https://doi.org/10.2147/TACG.S405120","url":null,"abstract":"<p><strong>Background: </strong><i>BRCA1</i> and <i>BRCA2</i> genes represent the most investigated breast and ovarian cancer predisposition genes. Ten cases of pathogenic de novo <i>BRCA1</i> variations and six cases of pathogenic de novo <i>BRCA2</i> variation have been reported at present. Here, we report a new case of a de novo <i>BRCA1</i> gene mutation.</p><p><strong>Case presentation: </strong>A 30-year-old woman with no health issues and no family history for hereditary breast and ovarian cancer was diagnosed with a hormone receptor positive/HER2 negative invasive breast cancer. Genetic testing revealed a pathogenic variant in <i>BRCA1</i> (c.4065_4068delTCAA) which was not found in her parents or sister.</p><p><strong>Conclusion: </strong>We report a new case of de novo <i>BRCA1</i> mutation, confirmed by repeated germline testing of the index patient and her parents. The published <i>BRCA1/2</i> de novo mutation rate is low. This is probably due - in part - to the strict testing criteria.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3d/bc/tacg-16-83.PMC10184889.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9480105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The introduction and development of genetic testing has caused the emergence of numerous dilemmas, which pertain to the performed tests, their results, and the influence they have on an individual person. To minimize potential doubts, it is crucial to ensure compliance with established procedures and to fulfill all test-associated formalities. In 2018, a report of the Polish Supreme Audit's Office (a governmental control agency) on the quality of genetic tests revealed that there is much to be done in the field of laboratory diagnostics in Poland. The inspection of six selected laboratories performing genetic tests identified shortcomings in terms of formalities accompanying the process of performing laboratory tests, keeping patient documentation and personal data protection. Although the observed shortcomings pertained to legal aspects of genetic tests, and not the quality of the tests themselves, the aforementioned may be detrimental to the individual person and the society (eg, lack of consent undermines the concept of biological material ownership), may cause legal liability to the laboratory personnel and even undermine public trust in genetic testing.
{"title":"Donor Safety, Discrepancies Between Practice and Theory: Analysis of the Polish Supreme Audit Office's Report.","authors":"Rafał Patryn, Anna Zagaja, Mariola Drozd","doi":"10.2147/TACG.S376251","DOIUrl":"https://doi.org/10.2147/TACG.S376251","url":null,"abstract":"<p><p>The introduction and development of genetic testing has caused the emergence of numerous dilemmas, which pertain to the performed tests, their results, and the influence they have on an individual person. To minimize potential doubts, it is crucial to ensure compliance with established procedures and to fulfill all test-associated formalities. In 2018, a report of the Polish Supreme Audit's Office (a governmental control agency) on the quality of genetic tests revealed that there is much to be done in the field of laboratory diagnostics in Poland. The inspection of six selected laboratories performing genetic tests identified shortcomings in terms of formalities accompanying the process of performing laboratory tests, keeping patient documentation and personal data protection. Although the observed shortcomings pertained to legal aspects of genetic tests, and not the quality of the tests themselves, the aforementioned may be detrimental to the individual person and the society (eg, lack of consent undermines the concept of biological material ownership), may cause legal liability to the laboratory personnel and even undermine public trust in genetic testing.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b1/5e/tacg-16-1.PMC9880020.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10585956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Agnes Stephanie Harahap, Imam Subekti, Sonar Soni Panigoro, Asmarinah, Lisnawati, Retno Asti Werdhani, Hasrayati Agustina, Dina Khoirunnisa, Mutiah Mutmainnah, Salinah, Alvita Dewi Siswoyo, Maria Francisca Ham
Introduction: BRAFV600E and RAS mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about BRAFV600E and RAS mutations in Indonesia. This study aims to determine the prevalence of BRAFV600E and RAS mutations, and their association with clinicopathologic characteristics.
Methods: Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for BRAFV600E, BRAFK601E, exon 2 and 3 of NRAS, HRAS, and KRAS. Analyses were performed to determine the associations of BRAFV600E and RAS mutations with clinicopathologic characteristics.
Results: Of 172 PTC patients, BRAFV600E mutation was observed in 37.8% of the patients and RAS mutations were found in 21.5%. One patient harbored BRAFK601E mutation. There was a significant association of BRAFV600E with a high-stage (p = 0.033, OR: 3.279; 95% CI: 1.048-10.259), tall-cell variants (p ≤0.001, OR: 41.143; 95% CI: 11.979-141.308), non-encapsulated (p = 0.001, OR: 4.176; 95% CI: 2.008-8.685), lymphovascular invasion (p = 0.043, OR: 1.912; 95% CI: 1.018-3.592), extrathyroidal extension (p = <0.001, OR: 3.983; 95% CI: 1.970-8.054), and lymph node metastasis (p = 0.009, OR: 2.301; 95% CI: 1.224-4.326). Follicular variant (p = 0.001, OR: 7.011; 95% CI: 2.690-18.268), encapsulated (p = 0.017, OR: 2.433; 95% CI: 1.161-5.100), and absent of extrathyroidal extension (p = 0.033, OR: 2.890; 95% CI: 1.052-7.940) were associated with RAS mutations.
Conclusion: A significant association between BRAFV600E mutation and high clinical stage, tall-cell variants, non-encapsulated morphology, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis in PTC was observed. RAS mutations were associated with the follicular variant, encapsulated tumor, and no extrathyroidal extension. HRAS-mutated PTC frequently exhibited tumor multifocality.
{"title":"Profile of <i>BRAF</i>V600E, <i>BRAF</i>K601E, <i>NRAS, HRAS</i>, and <i>KRAS</i> Mutational Status, and Clinicopathological Characteristics of Papillary Thyroid Carcinoma in Indonesian National Referral Hospital.","authors":"Agnes Stephanie Harahap, Imam Subekti, Sonar Soni Panigoro, Asmarinah, Lisnawati, Retno Asti Werdhani, Hasrayati Agustina, Dina Khoirunnisa, Mutiah Mutmainnah, Salinah, Alvita Dewi Siswoyo, Maria Francisca Ham","doi":"10.2147/TACG.S412364","DOIUrl":"https://doi.org/10.2147/TACG.S412364","url":null,"abstract":"<p><strong>Introduction: </strong><i>BRAF</i>V600E and <i>RAS</i> mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about <i>BRAF</i>V600E and <i>RAS</i> mutations in Indonesia. This study aims to determine the prevalence of <i>BRAF</i>V600E and <i>RAS</i> mutations, and their association with clinicopathologic characteristics.</p><p><strong>Methods: </strong>Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for <i>BRAF</i>V600E, <i>BRAF</i>K601E, exon 2 and 3 of <i>NRAS, HRAS</i>, and <i>KRAS</i>. Analyses were performed to determine the associations of <i>BRAF</i>V600E and <i>RAS</i> mutations with clinicopathologic characteristics.</p><p><strong>Results: </strong>Of 172 PTC patients, <i>BRAF</i>V600E mutation was observed in 37.8% of the patients and <i>RAS</i> mutations were found in 21.5%. One patient harbored <i>BRAF</i>K601E mutation. There was a significant association of <i>BRAF</i>V600E with a high-stage (p = 0.033, OR: 3.279; 95% CI: 1.048-10.259), tall-cell variants (p ≤0.001, OR: 41.143; 95% CI: 11.979-141.308), non-encapsulated (p = 0.001, OR: 4.176; 95% CI: 2.008-8.685), lymphovascular invasion (p = 0.043, OR: 1.912; 95% CI: 1.018-3.592), extrathyroidal extension (p = <0.001, OR: 3.983; 95% CI: 1.970-8.054), and lymph node metastasis (p = 0.009, OR: 2.301; 95% CI: 1.224-4.326). Follicular variant (p = 0.001, OR: 7.011; 95% CI: 2.690-18.268), encapsulated (p = 0.017, OR: 2.433; 95% CI: 1.161-5.100), and absent of extrathyroidal extension (p = 0.033, OR: 2.890; 95% CI: 1.052-7.940) were associated with <i>RAS</i> mutations.</p><p><strong>Conclusion: </strong>A significant association between <i>BRAF</i>V600E mutation and high clinical stage, tall-cell variants, non-encapsulated morphology, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis in PTC was observed. <i>RAS</i> mutations were associated with the follicular variant, encapsulated tumor, and no extrathyroidal extension. <i>HRAS</i>-mutated PTC frequently exhibited tumor multifocality.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f1/d7/tacg-16-99.PMC10226481.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9553553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Filippos Kyriakidis, Dionysios Kogias, Theodora Maria Venou, Eleni Karlafti, Daniel Paramythiotis
Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC). Having access to screening and enrollment programs can improve survival for patients with FAP by enabling them to undergo surgery before the development of colorectal cancer. Provided that there are a variety of surgical options available to treat colorectal polyps in patients with adenomatous polyposis, the appropriate surgical option for each patient should be considered. The gold-standard treatment to reduce this risk is prophylactic colectomy, typically by the age of 40. However, colectomy is linked to morbidity and constitutes an ineffective way at preventing extra-colonic disease manifestations, such as desmoid disease, thyroid malignancy, duodenal polyposis, and cancer. Moreover, extensive studies have been conducted into the use of chemopreventive agents to prevent disease progression and delay the necessity for a colectomy as well as the onset of extracolonic disease. The ideal chemoprevention agent should demonstrate a biologically plausible mechanism of action and provide safety, easy tolerance over an extended period of time and a lasting and clinically meaningful effect. Although many pharmaceutical and non-pharmaceutical products have been tested through the years, there has not yet been a chemoprevention agent that meets these criteria. Thus, it is necessary to develop new FAP agents that target novel pathways, such as the mTOR pathway. The aim of this article is to review the prior literature on FAP in order to concentrate the current and future perspectives of diagnosis and treatment. In conclusion, we will provide an update on the diagnostic and therapeutic options, surgical or pharmaceutical, while focusing on the potential treatment strategies that could further reduce the risk of CRC.
{"title":"Updated Perspectives on the Diagnosis and Management of Familial Adenomatous Polyposis.","authors":"Filippos Kyriakidis, Dionysios Kogias, Theodora Maria Venou, Eleni Karlafti, Daniel Paramythiotis","doi":"10.2147/TACG.S372241","DOIUrl":"https://doi.org/10.2147/TACG.S372241","url":null,"abstract":"<p><p>Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC). Having access to screening and enrollment programs can improve survival for patients with FAP by enabling them to undergo surgery before the development of colorectal cancer. Provided that there are a variety of surgical options available to treat colorectal polyps in patients with adenomatous polyposis, the appropriate surgical option for each patient should be considered. The gold-standard treatment to reduce this risk is prophylactic colectomy, typically by the age of 40. However, colectomy is linked to morbidity and constitutes an ineffective way at preventing extra-colonic disease manifestations, such as desmoid disease, thyroid malignancy, duodenal polyposis, and cancer. Moreover, extensive studies have been conducted into the use of chemopreventive agents to prevent disease progression and delay the necessity for a colectomy as well as the onset of extracolonic disease. The ideal chemoprevention agent should demonstrate a biologically plausible mechanism of action and provide safety, easy tolerance over an extended period of time and a lasting and clinically meaningful effect. Although many pharmaceutical and non-pharmaceutical products have been tested through the years, there has not yet been a chemoprevention agent that meets these criteria. Thus, it is necessary to develop new FAP agents that target novel pathways, such as the mTOR pathway. The aim of this article is to review the prior literature on FAP in order to concentrate the current and future perspectives of diagnosis and treatment. In conclusion, we will provide an update on the diagnostic and therapeutic options, surgical or pharmaceutical, while focusing on the potential treatment strategies that could further reduce the risk of CRC.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/72/54/tacg-16-139.PMC10439286.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10046627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Bilateral secondary angle closure glaucoma is a presenting symptom of microspherophakia and ectopia lentis. Characterizing the associated syndrome and confirmation by genetic testing can identify associated systemic abnormalities and provide appropriate genetic counseling.
Case presentation: A 42-year-old woman with severe intellectual disability presented with light perception visual acuity and glaucoma, with intraocular pressure (IOP) in her right and left eyes of 69 and 70 mmHg, respectively. She underwent two sessions of 270-degree laser diode transscleral cytophotocoagulation treatment at a 6-month interval and was prescribed topical anti-glaucoma medication. Her family noticed a progressive decrease in her vision while on treatment for 2 years. She was diagnosed with apparent Weill-Marchesani syndrome, accompanied by angle closure glaucoma and microspherophakia. Cataract surgery and intraocular lens implantation were successful in both eyes and post-operative IOP was controlled with anti-glaucoma medication but her vision did not improve from severe glaucomatous optic neuropathy. Her underlying syndrome was investigated genetically by whole exome sequencing.
Results: Sequencing showed a pathogenic variant in ARID1B, c.3955dupC (p.Gln1319Profs*14), diagnostic of Coffin-Siris syndrome. This is the first report of Coffin-Siris syndrome associated with microspherophakia and angle closure glaucoma.
Conclusion: Bilateral angle closure glaucoma from ectopia lentis in patients with genetic syndromes could be an indicator of microspherophakia in adulthood. Ophthalmological surveillance is important in patients with Coffin-Siris syndrome.
{"title":"Microspherophakic Angle Closure Glaucoma in a Patient with Coffin-Siris Syndrome: Case Report.","authors":"Kulawan Rojananuangnit, Kitiwan Rojnueangnit","doi":"10.2147/TACG.S422312","DOIUrl":"https://doi.org/10.2147/TACG.S422312","url":null,"abstract":"<p><strong>Background: </strong>Bilateral secondary angle closure glaucoma is a presenting symptom of microspherophakia and ectopia lentis. Characterizing the associated syndrome and confirmation by genetic testing can identify associated systemic abnormalities and provide appropriate genetic counseling.</p><p><strong>Case presentation: </strong>A 42-year-old woman with severe intellectual disability presented with light perception visual acuity and glaucoma, with intraocular pressure (IOP) in her right and left eyes of 69 and 70 mmHg, respectively. She underwent two sessions of 270-degree laser diode transscleral cytophotocoagulation treatment at a 6-month interval and was prescribed topical anti-glaucoma medication. Her family noticed a progressive decrease in her vision while on treatment for 2 years. She was diagnosed with apparent Weill-Marchesani syndrome, accompanied by angle closure glaucoma and microspherophakia. Cataract surgery and intraocular lens implantation were successful in both eyes and post-operative IOP was controlled with anti-glaucoma medication but her vision did not improve from severe glaucomatous optic neuropathy. Her underlying syndrome was investigated genetically by whole exome sequencing.</p><p><strong>Results: </strong>Sequencing showed a pathogenic variant in <i>ARID1B</i>, c.3955dupC (p.Gln1319Profs*14), diagnostic of Coffin-Siris syndrome. This is the first report of Coffin-Siris syndrome associated with microspherophakia and angle closure glaucoma.</p><p><strong>Conclusion: </strong>Bilateral angle closure glaucoma from ectopia lentis in patients with genetic syndromes could be an indicator of microspherophakia in adulthood. Ophthalmological surveillance is important in patients with Coffin-Siris syndrome.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2c/72/tacg-16-165.PMC10474847.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10154719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}