Pub Date : 2021-02-11eCollection Date: 2021-01-01DOI: 10.2147/TACG.S276596
Nastaran Asri, Mohammad Rostami-Nejad, Robert P Anderson, Kamran Rostami
Wheat flour is one of the most important food ingredients containing several essential nutrients including proteins. Gluten is one of the major protein components of wheat consisted of glutenin (encoded on chromosome 1) and gliadin (encoded on chromosome 1 and 6) and there are around hundred genes encoding it in wheat. Gluten proteins have the ability of eliciting the pathogenic immune responses and hypersensitivity reactions in susceptible individuals called "gluten-related disorders (GRDs)", which include celiac disease (CD), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS). Currently removing gluten from the diet is the only effective treatment for mentioned GRDs and studies for the appropriate and alternative therapeutic approaches are ongoing. Accordingly, several genetic studies have focused on breeding wheat with low immunological properties through gene editing methods. The present review considers genetic characteristics of gluten protein components, focusing on their role in the incidence of gluten-related diseases, and genetic modifications conducted to produce wheat with less immunological properties.
{"title":"The Gluten Gene: Unlocking the Understanding of Gluten Sensitivity and Intolerance.","authors":"Nastaran Asri, Mohammad Rostami-Nejad, Robert P Anderson, Kamran Rostami","doi":"10.2147/TACG.S276596","DOIUrl":"https://doi.org/10.2147/TACG.S276596","url":null,"abstract":"<p><p>Wheat flour is one of the most important food ingredients containing several essential nutrients including proteins. Gluten is one of the major protein components of wheat consisted of glutenin (encoded on chromosome 1) and gliadin (encoded on chromosome 1 and 6) and there are around hundred genes encoding it in wheat. Gluten proteins have the ability of eliciting the pathogenic immune responses and hypersensitivity reactions in susceptible individuals called \"gluten-related disorders (GRDs)\", which include celiac disease (CD), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS). Currently removing gluten from the diet is the only effective treatment for mentioned GRDs and studies for the appropriate and alternative therapeutic approaches are ongoing. Accordingly, several genetic studies have focused on breeding wheat with low immunological properties through gene editing methods. The present review considers genetic characteristics of gluten protein components, focusing on their role in the incidence of gluten-related diseases, and genetic modifications conducted to produce wheat with less immunological properties.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2021-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/72/39/tacg-14-37.PMC7886246.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25382845","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}
Pub Date : 2021-02-09eCollection Date: 2021-01-01DOI: 10.2147/TACG.S278652
Tran Thu Ha Pham, Quang Binh Tran, Chonlaphat Sukasem, Van Dinh Nguyen, Chi Hieu Chu, Thi Quynh Nga Do, Ngoc Phuong Mai Tran, Thanh Huong Phung
Background: Allopurinol, a common anti-hyperuricemia drug, is well known as an inducer of severe cutaneous adverse drug reactions (SCARs). One of the most well-defined risk factors of allopurinol-induced SCARs is the presence of polymorphic alleles of human leukocyte antigen (HLA) genes, such as HLA-B*58:01 and HLA-C*03:02 alleles. There is no commercial test or published in-house protocol for the specific detection of the HLA-C*03:02 allele. In this article, we established for the first time a simple allele-specific (AS) PCR method to identify HLA-C*03:02 allele carriers, and at the same time, determine their zygosities.
Methods: A two-step AS-PCR protocol, using four primer sets, was designed to specifically amplify and differentiate the HLA-C*03:02 allele from 17 other HLA-C alleles found in Vietnamese people. The protocol was validated with PCR-sequencing-based typing (SBT) of 100 samples of unknown genotypes.
Results: The PCR protocol can detect the HLA-C*03:02 allele and determine the zygosity. The results of this protocol were highly consistent with those of the SBT (ĸ = 0.98, p < 0.001). Regarding the specific detection of the HLA-C*03:02 allele, the PCR protocol had a sensitivity of 100% (95% CI: 91.61-100%) and specificity of 98.3% (95% CI: 90.9-99.7%). The protocol was used to determine the distribution of the HLA-C*03:02 allele in 810 unrelated Vietnamese Kinh people, 14.2% of which were HLA-C*03:02 carriers, the allele frequency was 7.5%.
Conclusion: A novel AS-PCR protocol with a sensitivity of 100% for the detection of the HLA-C*03:02 allele was established. The protocol can be used for personalized treatment with allopurinol in order to minimize the risk of SCARs in Vietnamese people as well as in other Asian populations with similar genetic characteristics.
背景:别嘌呤醇是一种常见的抗高尿酸血症药物,被认为是严重皮肤药物不良反应(scar)的诱导剂。别嘌呤醇诱导的疤痕最明确的危险因素之一是人类白细胞抗原(HLA)基因多态性等位基因的存在,如HLA- b *58:01和HLA- c *03:02等位基因。目前还没有针对HLA-C*03:02等位基因特异性检测的商业测试或公开的内部方案。在本文中,我们首次建立了一种简单的等位基因特异性(AS) PCR方法来鉴定HLA-C*03:02等位基因携带者,同时测定其合子。方法:采用四组引物,设计两步AS-PCR技术,特异扩增和区分越南人HLA-C*03:02等位基因和其他17个HLA-C等位基因。对100个未知基因型样本进行了基于pcr测序的分型(SBT)验证。结果:PCR方法能检测到HLA-C*03:02等位基因并确定合子性。该方案的结果与SBT的结果高度一致( = 0.98, p < 0.001)。对于HLA-C*03:02等位基因的特异性检测,PCR方案的灵敏度为100% (95% CI: 91.61 ~ 100%),特异性为98.3% (95% CI: 90.9 ~ 99.7%)。采用该方案测定了810例越南京族无亲缘关系人群HLA-C*03:02等位基因的分布,其中14.2%为HLA-C*03:02携带者,等位基因频率为7.5%。结论:建立了一种检测HLA-C*03:02等位基因灵敏度为100%的AS-PCR新方法。该方案可用于别嘌呤醇的个性化治疗,以尽量减少越南人民以及具有相似遗传特征的其他亚洲人群发生疤痕的风险。
{"title":"A Novel Allele-Specific PCR Protocol for the Detection of the <i>HLA-C*03:02</i> Allele, a Pharmacogenetic Marker, in Vietnamese Kinh People.","authors":"Tran Thu Ha Pham, Quang Binh Tran, Chonlaphat Sukasem, Van Dinh Nguyen, Chi Hieu Chu, Thi Quynh Nga Do, Ngoc Phuong Mai Tran, Thanh Huong Phung","doi":"10.2147/TACG.S278652","DOIUrl":"https://doi.org/10.2147/TACG.S278652","url":null,"abstract":"<p><strong>Background: </strong>Allopurinol, a common anti-hyperuricemia drug, is well known as an inducer of severe cutaneous adverse drug reactions (SCARs). One of the most well-defined risk factors of allopurinol-induced SCARs is the presence of polymorphic alleles of human leukocyte antigen (<i>HLA</i>) genes, such as <i>HLA-B*58:01</i> and <i>HLA-C*03:02</i> alleles. There is no commercial test or published in-house protocol for the specific detection of the <i>HLA-C*03:02</i> allele. In this article, we established for the first time a simple allele-specific (AS) PCR method to identify <i>HLA-C*03:02</i> allele carriers, and at the same time, determine their zygosities.</p><p><strong>Methods: </strong>A two-step AS-PCR protocol, using four primer sets, was designed to specifically amplify and differentiate the <i>HLA-C*03:02</i> allele from 17 other <i>HLA-C</i> alleles found in Vietnamese people. The protocol was validated with PCR-sequencing-based typing (SBT) of 100 samples of unknown genotypes.</p><p><strong>Results: </strong>The PCR protocol can detect the <i>HLA-C*03:02</i> allele and determine the zygosity. The results of this protocol were highly consistent with those of the SBT (ĸ = 0.98, p < 0.001). Regarding the specific detection of the <i>HLA-C*03:02</i> allele, the PCR protocol had a sensitivity of 100% (95% CI: 91.61-100%) and specificity of 98.3% (95% CI: 90.9-99.7%). The protocol was used to determine the distribution of the <i>HLA-C*03:02</i> allele in 810 unrelated Vietnamese Kinh people, 14.2% of which were <i>HLA-C*03:02</i> carriers, the allele frequency was 7.5%.</p><p><strong>Conclusion: </strong>A novel AS-PCR protocol with a sensitivity of 100% for the detection of the <i>HLA-C*03:02</i> allele was established. The protocol can be used for personalized treatment with allopurinol in order to minimize the risk of SCARs in Vietnamese people as well as in other Asian populations with similar genetic characteristics.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2021-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/f5/tacg-14-27.PMC7881795.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25382370","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}
Pub Date : 2021-01-25eCollection Date: 2021-01-01DOI: 10.2147/TACG.S239603
Melissa C Keinath, Devin E Prior, Thomas W Prior
Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.
{"title":"Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance.","authors":"Melissa C Keinath, Devin E Prior, Thomas W Prior","doi":"10.2147/TACG.S239603","DOIUrl":"https://doi.org/10.2147/TACG.S239603","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene <i>SMN1</i> on 5q13 but keep the modifying <i>SMN2</i> gene. The most common mutation causing SMA is a homozygous deletion of the <i>SMN1</i> exon 7, which can be readily detected and used as a sensitive diagnostic test. Because <i>SMN2</i> produces a reduced number of full-length transcripts, the number of <i>SMN2</i> copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the <i>SMN2</i> transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters <i>SMN2</i> splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2021-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ab/a3/tacg-14-11.PMC7846873.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25324507","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}
Pub Date : 2021-01-14eCollection Date: 2021-01-01DOI: 10.2147/TACG.S245021
Lindsey McAlarnen, Kristen Stearns, Denise Uyar
Completion of genetic testing is increasingly important for the complex care of patients with suspected hereditary breast and ovarian cancers (HBOC) and their at-risk family members. Identification of individuals with pathogenic variants has implications for targeted treatment recommendations, risk reduction strategies, increased surveillance recommendations, as well as the genetic testing of family members, known as cascade testing or screening. Due to advances in technology and decreasing costs, what was once single-gene genetic testing has evolved into large-scale multi-gene panel genomic testing. As germline genomic testing for HBOC becomes more and more available, it is important to identify the challenges that are associated with its use. In this manuscript, we review the current issues faced by germline genomic testing for HBOC which include effectively managing the marked increases in genetic referrals, interpreting the vast amount of information yielded by newer testing methods such as next generation sequencing (NGS), recognizing the need for better cascade screening strategies, potential exacerbation of health disparities and improving support for patients navigating the emotional impact related to positive, negative and indeterminate testing results.
{"title":"Challenges of Genomic Testing for Hereditary Breast and Ovarian Cancers.","authors":"Lindsey McAlarnen, Kristen Stearns, Denise Uyar","doi":"10.2147/TACG.S245021","DOIUrl":"10.2147/TACG.S245021","url":null,"abstract":"<p><p>Completion of genetic testing is increasingly important for the complex care of patients with suspected hereditary breast and ovarian cancers (HBOC) and their at-risk family members. Identification of individuals with pathogenic variants has implications for targeted treatment recommendations, risk reduction strategies, increased surveillance recommendations, as well as the genetic testing of family members, known as cascade testing or screening. Due to advances in technology and decreasing costs, what was once single-gene genetic testing has evolved into large-scale multi-gene panel genomic testing. As germline genomic testing for HBOC becomes more and more available, it is important to identify the challenges that are associated with its use. In this manuscript, we review the current issues faced by germline genomic testing for HBOC which include effectively managing the marked increases in genetic referrals, interpreting the vast amount of information yielded by newer testing methods such as next generation sequencing (NGS), recognizing the need for better cascade screening strategies, potential exacerbation of health disparities and improving support for patients navigating the emotional impact related to positive, negative and indeterminate testing results.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2021-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6d/d6/tacg-14-1.PMC7814235.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38853190","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}
Pub Date : 2020-12-18eCollection Date: 2020-01-01DOI: 10.2147/TACG.S282843
Amany A Saleh, Safaa I Tayel, Awny Gamal Shalaby, Sherin Sobhy El Naidany
Background and aim: Genetic factors are vital participants in the development and progression of myocardial infarction (MI). Adiponectin has been assumed to have a protective role in MI and adiponectin receptors variants could be a determinant for atherosclerosis. We aimed to evaluate the prevalence of ADIPOQ (rs2241766) and ADIPOR2 (rs10773989) polymorphisms and their association with mRNA levels and circulatory adiponectin levels in patients with MI.
Subjects and methods: A total of 220 participants were classified into two groups: group 1 included 120 patients with MI, and group 2 involved 100 healthy participants as controls. Genotyping of ADIPOQ (rs2241766) and ADIPOR2 (rs10773989) polymorphisms were analyzed using an allele discrimination assay with real-time PCR and their relative expression or mRNA levels were determined by real-time PCR. Serum adiponectin level was determined using an ELISA technique.
Results: The ADIPOQ rs2241766 GG genotype and G allele and the CC genotype and C allele of ADIPOR2 rs10773989 were significantly prevalent in patients with MI and associated with increased risk of MI. We detected a marked reduction in serum adiponectin, ADIPOQ and ADIPOR2 mRNA levels in patients than control. The GG genotype of ADIPOQ rs2241766 and the CC genotype of ADIPOR2 rs10773989 had the lowest levels of their mRNA and adiponectin level in both patients and controls.
Conclusion: Adiponectin gene and receptor variants are potentially related to MI risk; furthermore, their expressions were markedly depressed in MI which suggests their use as potential biomarkers for MI.
{"title":"Role of Adiponectin Gene and Receptor Polymorphisms and Their mRNA Levels with Serum Adiponectin Level in Myocardial Infarction.","authors":"Amany A Saleh, Safaa I Tayel, Awny Gamal Shalaby, Sherin Sobhy El Naidany","doi":"10.2147/TACG.S282843","DOIUrl":"https://doi.org/10.2147/TACG.S282843","url":null,"abstract":"<p><strong>Background and aim: </strong>Genetic factors are vital participants in the development and progression of myocardial infarction (MI). Adiponectin has been assumed to have a protective role in MI and adiponectin receptors variants could be a determinant for atherosclerosis. We aimed to evaluate the prevalence of <i>ADIPOQ</i> (rs2241766) and <i>ADIPOR2</i> (rs10773989) polymorphisms and their association with mRNA levels and circulatory adiponectin levels in patients with MI.</p><p><strong>Subjects and methods: </strong>A total of 220 participants were classified into two groups: group 1 included 120 patients with MI, and group 2 involved 100 healthy participants as controls. Genotyping of <i>ADIPOQ</i> (rs2241766) and <i>ADIPOR2</i> (rs10773989) polymorphisms were analyzed using an allele discrimination assay with real-time PCR and their relative expression or mRNA levels were determined by real-time PCR. Serum adiponectin level was determined using an ELISA technique.</p><p><strong>Results: </strong>The <i>ADIPOQ</i> rs2241766 GG genotype and G allele and the CC genotype and C allele of <i>ADIPOR2</i> rs10773989 were significantly prevalent in patients with MI and associated with increased risk of MI. We detected a marked reduction in serum adiponectin, ADIPOQ and ADIPOR2 mRNA levels in patients than control. The GG genotype of <i>ADIPOQ</i> rs2241766 and the CC genotype of <i>ADIPOR2</i> rs10773989 had the lowest levels of their mRNA and adiponectin level in both patients and controls.</p><p><strong>Conclusion: </strong>Adiponectin gene and receptor variants are potentially related to MI risk; furthermore, their expressions were markedly depressed in MI which suggests their use as potential biomarkers for MI.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2020-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fa/1f/tacg-13-241.PMC7755379.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38763699","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}
Pub Date : 2020-12-17eCollection Date: 2020-01-01DOI: 10.2147/TACG.S282240
Camilo Andres Velandia-Piedrahita, Adrien Morel, Dora Janeth Fonseca-Mendoza, Victor Manuel Huertas-Quiñones, David Castillo, Juan Diego Bonilla, Camilo José Hernandez-Toro, Marta Catalina Miranda-Fernández, Carlos Martin Restrepo, Rodrigo Cabrera
The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of ELN. The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.
{"title":"A Novel Splice-Site Mutation in the <i>ELN</i> Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.","authors":"Camilo Andres Velandia-Piedrahita, Adrien Morel, Dora Janeth Fonseca-Mendoza, Victor Manuel Huertas-Quiñones, David Castillo, Juan Diego Bonilla, Camilo José Hernandez-Toro, Marta Catalina Miranda-Fernández, Carlos Martin Restrepo, Rodrigo Cabrera","doi":"10.2147/TACG.S282240","DOIUrl":"https://doi.org/10.2147/TACG.S282240","url":null,"abstract":"<p><p>The <i>ELN</i> gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the <i>ELN</i> gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of <i>ELN</i>. The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2c/f2/tacg-13-233.PMC7751611.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38752745","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}
Purpose: Four consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis.
Patients and methods: Members from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation.
Results: We had a 100% success rate identifying each case presented in this study.
Conclusion: This is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.
{"title":"Effect of Genetic Testing on Diagnosing Gastrointestinal Pediatric Patients with Previously Undiagnosed Diseases.","authors":"Eyad Altamimi, Mariam Khanfar, Omar Rabab'h, Zain Dardas, Luma Srour, Lina Mustafa, Bilal Azab","doi":"10.2147/TACG.S275992","DOIUrl":"https://doi.org/10.2147/TACG.S275992","url":null,"abstract":"<p><strong>Purpose: </strong>Four consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis.</p><p><strong>Patients and methods: </strong>Members from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation.</p><p><strong>Results: </strong>We had a 100% success rate identifying each case presented in this study.</p><p><strong>Conclusion: </strong>This is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2020-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0e/eb/tacg-13-221.PMC7751587.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38752744","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}
Pub Date : 2020-12-14eCollection Date: 2020-01-01DOI: 10.2147/TACG.S281872
Tandi E Matsha, Shanel Raghubeer, Abegail M Tshivhase, Saarah F G Davids, Gloudina M Hon, Lise Bjørkhaug, Rajiv T Erasmus
Background and aim: Maturity-onset diabetes of the young (MODY) is the result of single gene variants. To date, fourteen different MODY subtypes have been described. Variants in genes coding for glucokinase (GCK, MODY2) and hepatic nuclear factor 1 alpha (HNF1A, MODY3) are most frequently encountered. MODY patients are often misdiagnosed with type 1 or type 2 diabetes, resulting in incorrect treatment protocols. At the time of reporting, no data are available on MODY prevalence in populations from Africa. Our study aimed to investigate and report on the incidence of MODY-related variants, specifically HNF1A variants, in a population from the Western Cape.
Methods: Study participants were recruited (1643 in total, 407 males, 1236 females) and underwent anthropometric tests. Thereafter, blood was collected, and real-time PCR was used to screen for specific variants in HNF1A and GCK genes.
Results: Ninety-seven individuals (5.9%) were identified with a specific HNF1A gene polymorphism (rs1169288) and twelve (0.9%) with a GCK polymorphism (rs4607517).
Conclusion: In total, 6.6% of the study population expressed MODY variants. To our knowledge, we are the first to report on MODY incidence in Africa. This research provides the basis for MODY incidence studies in South Africa, as well as data on non-Caucasian populations.
{"title":"Incidence of <i>HNF1A</i> and <i>GCK</i> MODY Variants in a South African Population.","authors":"Tandi E Matsha, Shanel Raghubeer, Abegail M Tshivhase, Saarah F G Davids, Gloudina M Hon, Lise Bjørkhaug, Rajiv T Erasmus","doi":"10.2147/TACG.S281872","DOIUrl":"10.2147/TACG.S281872","url":null,"abstract":"<p><strong>Background and aim: </strong>Maturity-onset diabetes of the young (MODY) is the result of single gene variants. To date, fourteen different MODY subtypes have been described. Variants in genes coding for glucokinase (<i>GCK</i>, MODY2) and hepatic nuclear factor 1 alpha (<i>HNF1A</i>, MODY3) are most frequently encountered. MODY patients are often misdiagnosed with type 1 or type 2 diabetes, resulting in incorrect treatment protocols. At the time of reporting, no data are available on MODY prevalence in populations from Africa. Our study aimed to investigate and report on the incidence of MODY-related variants, specifically <i>HNF1A</i> variants, in a population from the Western Cape.</p><p><strong>Methods: </strong>Study participants were recruited (1643 in total, 407 males, 1236 females) and underwent anthropometric tests. Thereafter, blood was collected, and real-time PCR was used to screen for specific variants in <i>HNF1A</i> and <i>GCK</i> genes.</p><p><strong>Results: </strong>Ninety-seven individuals (5.9%) were identified with a specific <i>HNF1A</i> gene polymorphism (rs1169288) and twelve (0.9%) with a <i>GCK</i> polymorphism (rs4607517).</p><p><strong>Conclusion: </strong>In total, 6.6% of the study population expressed MODY variants. To our knowledge, we are the first to report on MODY incidence in Africa. This research provides the basis for MODY incidence studies in South Africa, as well as data on non-Caucasian populations.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2020-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ab/74/tacg-13-209.PMC7754620.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39087343","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}
Gene therapy has now evolved as the upcoming modality for management of many disorders, both inheritable and non-inheritable. Knowledge of genetics pertaining to a disease has therefore become paramount for physicians across most specialities. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber's congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Research in gene therapy has led to the development and approval of voretigene neparvovec (VN) for use in patients of LCA with a deficient biallelic RPE65 gene. The procedure involves delivery of a recombinant virus vector that carries the RPE65 gene in the subretinal space. This comprehensive review reports the evidence thus far in support of gene therapy for LCA. We explore and compare the various gene targets including but not limited to RPE65, and discuss the choice of vector and method for ocular delivery. The review details the evolution of gene therapy with VN in a phased manner, concluding with the challenges that lie ahead for its translation for use in communities that differ much both genetically and economically.
{"title":"Voretigene Neparvovec and Gene Therapy for Leber's Congenital Amaurosis: Review of Evidence to Date.","authors":"Srikanta Kumar Padhy, Brijesh Takkar, Raja Narayanan, Pradeep Venkatesh, Subhadra Jalali","doi":"10.2147/TACG.S230720","DOIUrl":"https://doi.org/10.2147/TACG.S230720","url":null,"abstract":"<p><p>Gene therapy has now evolved as the upcoming modality for management of many disorders, both inheritable and non-inheritable. Knowledge of genetics pertaining to a disease has therefore become paramount for physicians across most specialities. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber's congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Research in gene therapy has led to the development and approval of voretigene neparvovec (VN) for use in patients of LCA with a deficient biallelic <i>RPE65</i> gene. The procedure involves delivery of a recombinant virus vector that carries the <i>RPE65</i> gene in the subretinal space. This comprehensive review reports the evidence thus far in support of gene therapy for LCA. We explore and compare the various gene targets including but not limited to <i>RPE65</i>, and discuss the choice of vector and method for ocular delivery. The review details the evolution of gene therapy with VN in a phased manner, concluding with the challenges that lie ahead for its translation for use in communities that differ much both genetically and economically.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2020-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S230720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38667292","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}
Pub Date : 2020-11-19eCollection Date: 2020-01-01DOI: 10.2147/TACG.S281502
Mona S Habieb, Ashraf A Dawood, Mahmoud M Emara, Mohammad G Elhelbawy, Nesreen G Elhelbawy
Background: Diabetic nephropathy (DN), the primary driver of end-stage kidney disease, is a problem with serious consequences for society's health. Single nucleotide polymorphisms (SNPs) can define differences in susceptibility to DN and aid in development of personalized treatment. Giving the importance of epoxyeicosatrienoic acids (EETs) in kidney health, we aimed to study the association between two SNPs in the genes controlling synthesis and degradation of EETs (CYP2J2 rs2280275 and EPHX2 rs751141 respectively) and susceptibility of type 2 diabetes mellitus (T2DM) patients to develop DN.
Patients and methods: Two hundred subjects were enrolled and categorized into three groups: group I (80 T2DM patients with DN), group II (60 T2DM patients without DN) and group III (60 healthy controls). Urea, creatinine, albumin/creatinine ratio (ACR), and eGFR were measured for all participants. Genotyping of CYP2J2 rs2280275 and EPHX2 rs751141 was done by real time PCR.
Results: There was no significant difference between the studied groups regarding CYP2J2 rs2280275. In contrast, EPHX2 rs751141 was associated with increased risk of DN under a dominant model (GG vs GA+AA: OR=0.375; 95% CI (0.19-0.75), P=0.006) in unadjusted model and after adjustment for age and sex (OR=0.440; 95% CI (0.21-0.92), P=0.029), recessive model (AA vs GG+GA: OR=0.195; 95% CI (0.05-0.74), P=0.017) and additive model (GA vs GG+AA): OR=0.195; 95% CI (0.05-0.74), P=0.017).
Conclusion: CYP2J2 rs2280275 was not associated with DN predisposition. However, EPHX2 rs751141 could be a genetic marker for development and progression of DN among Egyptian T2DM patients.
背景:糖尿病肾病(DN)是终末期肾病的主要诱因,是一个严重影响社会健康的问题。单核苷酸多态性(SNPs)可确定糖尿病肾病易感性的差异,并有助于开发个性化治疗方法。鉴于环二十碳三烯酸(EETs)对肾脏健康的重要性,我们旨在研究控制 EETs 合成和降解的基因中的两个 SNPs(分别为 CYP2J2 rs2280275 和 EPHX2 rs751141)与 2 型糖尿病(T2DM)患者对 DN 的易感性之间的关系:200 名受试者分为三组:第一组(80 名患有 DN 的 T2DM 患者)、第二组(60 名未患有 DN 的 T2DM 患者)和第三组(60 名健康对照组)。对所有参与者的尿素、肌酐、白蛋白/肌酐比值(ACR)和 eGFR 进行了测量。通过实时 PCR 对 CYP2J2 rs2280275 和 EPHX2 rs751141 进行了基因分型:结果:研究组之间在 CYP2J2 rs2280275 方面没有明显差异。相反,在显性模型下,EPHX2 rs751141 与 DN 风险增加有关(GG vs GA+AA:在未调整模型中,OR=0.375;95% CI (0.19-0.75),P=0.006;在调整年龄和性别(OR=0.440;95% CI (0.21-0.92),P=0.029)、隐性模型(AA vs GG+GA:OR=0.195;95% CI (0.05-0.74),P=0.017)和加性模型(GA vs GG+AA)后,OR=0.195;95% CI (0.05-0.74),P=0.017:OR=0.195;95% CI (0.05-0.74),P=0.017):结论:CYP2J2 rs2280275与DN易感性无关。结论:CYP2J2 rs2280275与DN易感性无关,但EPHX2 rs751141可能是埃及T2DM患者DN发生和发展的遗传标记。
{"title":"The Human Genetic Variants CYP2J2 rs2280275 and EPHX2 rs751141 and Risk of Diabetic Nephropathy in Egyptian Type 2 Diabetic Patients.","authors":"Mona S Habieb, Ashraf A Dawood, Mahmoud M Emara, Mohammad G Elhelbawy, Nesreen G Elhelbawy","doi":"10.2147/TACG.S281502","DOIUrl":"10.2147/TACG.S281502","url":null,"abstract":"<p><strong>Background: </strong>Diabetic nephropathy (DN), the primary driver of end-stage kidney disease, is a problem with serious consequences for society's health. Single nucleotide polymorphisms (SNPs) can define differences in susceptibility to DN and aid in development of personalized treatment. Giving the importance of epoxyeicosatrienoic acids (EETs) in kidney health, we aimed to study the association between two SNPs in the genes controlling synthesis and degradation of EETs <i>(CYP2J2</i> rs2280275 and <i>EPHX2</i> rs751141 respectively) and susceptibility of type 2 diabetes mellitus (T2DM) patients to develop DN.</p><p><strong>Patients and methods: </strong>Two hundred subjects were enrolled and categorized into three groups: group I (80 T2DM patients with DN), group II (60 T2DM patients without DN) and group III (60 healthy controls). Urea, creatinine, albumin/creatinine ratio (ACR), and eGFR were measured for all participants. Genotyping of <i>CYP2J2</i> rs2280275 and <i>EPHX2</i> rs751141 was done by real time PCR.</p><p><strong>Results: </strong>There was no significant difference between the studied groups regarding <i>CYP2J2</i> rs2280275. In contrast, <i>EPHX2</i> rs751141 was associated with increased risk of DN under a dominant model (GG vs GA+AA: OR=0.375; 95% CI (0.19-0.75), P=0.006) in unadjusted model and after adjustment for age and sex (OR=0.440; 95% CI (0.21-0.92), P=0.029), recessive model (AA vs GG+GA: OR=0.195; 95% CI (0.05-0.74), P=0.017) and additive model (GA vs GG+AA): OR=0.195; 95% CI (0.05-0.74), P=0.017).</p><p><strong>Conclusion: </strong><i>CYP2J2</i> rs2280275 was not associated with DN predisposition. However, <i>EPHX2</i> rs751141 could be a genetic marker for development and progression of DN among Egyptian T2DM patients.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2020-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/22/90/tacg-13-165.PMC7682612.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38642280","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}