The Application of Clinical Genetics最新文献

{"title":"A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer.","authors":"Bradley King,&nbsp;Jana McHugh,&nbsp;Katie Snape","doi":"10.2147/TACG.S261737","DOIUrl":"https://doi.org/10.2147/TACG.S261737","url":null,"abstract":"<p><p><i>BRCA2</i> is the most commonly implicated DNA damage repair gene associated with inherited prostate cancer. <i>BRCA2</i> deficient prostate cancer typically presents at a younger age, is more poorly differentiated, and is associated with worse survival outcomes than non-<i>BRCA2</i> associated prostate cancer. Despite these unfavourable prognostic implications, poly-ADP ribose polymerase inhibitors and platinum-based chemotherapy have been identified as potent targeted therapeutic agents towards <i>BRCA1/2</i> deficient cancer cells. This review article explores the literature surrounding <i>BRCA2</i>-related prostate cancer through a familial clinical scenario. The investigation, diagnosis and management of <i>BRCA2</i> deficient prostate cancer will be explored, alongside the implications of the identification of a germline pathogenic <i>BRCA2</i> variant within a family, cascade screening and prostate cancer surveillance in unaffected male <i>BRCA2</i> carriers. A greater understanding of the molecular pathogenesis of DNA damage repair gene deficient prostate cancer, coupled with new treatment paradigms and widened access to both somatic and germline genetic analysis for prostate cancer patients and their families will hopefully enable the robust implementation of high quality evidence-based clinical pathways for both the management and identification of <i>BRCA2</i> deficient prostate cancer and improved screening, early detection and prevention strategies for individuals at increased genetic risk of prostate cancer.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"255-266"},"PeriodicalIF":3.1,"publicationDate":"2021-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e9/f8/tacg-14-255.PMC8290889.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39210543","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}

{"title":"Genetic Predictors of Mortality in Patients with Multiple Myeloma.","authors":"Hamza Hassan,&nbsp;Raphael Szalat","doi":"10.2147/TACG.S262866","DOIUrl":"https://doi.org/10.2147/TACG.S262866","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a heterogeneous disease featured by clonal plasma cell proliferation and genomic instability. The advent of next-generation sequencing allowed unraveling the complex genomic landscape of the disease. Several recurrent genomic aberrations including immunoglobulin genes translocations, copy number abnormalities, complex chromosomal events, transcriptomic and epigenomic deregulation, and mutations define various molecular subgroups with distinct outcomes. In this review, we describe the recurrent genomic events identified in MM impacting patients' outcome and survival. These genomic aberrations constitute new markers that could be incorporated into a prognostication model to eventually guide therapy at every stage of the disease.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"241-254"},"PeriodicalIF":3.1,"publicationDate":"2021-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6d/50/tacg-14-241.PMC8092627.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38952541","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}

{"title":"Pseudo-Meigs' Syndrome in Tunisian H Syndrome Female Patient: First Case Reported.","authors":"Yosra Zaimi,&nbsp;Myriam Ayari,&nbsp;Asma Mensi,&nbsp;Linda Bel Hadj Kacem,&nbsp;Leila Achouri,&nbsp;Meriem Bouzrara,&nbsp;Yosra Said,&nbsp;Leila Mouelhi,&nbsp;Radhouane Debbeche","doi":"10.2147/TACG.S306298","DOIUrl":"https://doi.org/10.2147/TACG.S306298","url":null,"abstract":"<p><p>H syndrome is an extremely rare autosomal recessive affection caused by biallelic mutations in the SLC29A3 gene encoding the human equilibrative nucleoside transporter hENT3. The hallmark signs are cutaneous consisting of hyperpigmentation and hypertrichosis patches. Besides, associated systemic manifestations are highly various reflecting phenotypic pleiotropism. Herein, we report a first case of pseudo-Meigs' syndrome occurring in a young Tunisian H syndrome diagnosed patient with a novel homozygous frameshift mutation in exon 2 of the SLC29A3 gene: p.S15Pfs*86 inducing a premature stop codon. The patient developed ascites associated with left ovarian mass and she underwent surgery. After tumor resection, ascites disappeared rapidly. Histological examination showed serous cystadenoma of the ovary orienting the diagnosis towards pseudo-Meigs' syndrome.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"235-239"},"PeriodicalIF":3.1,"publicationDate":"2021-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/67/37/tacg-14-235.PMC8055247.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38895841","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}

{"title":"The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia.","authors":"Daniel W Sirkis,&nbsp;Luke W Bonham,&nbsp;Jennifer S Yokoyama","doi":"10.2147/TACG.S245029","DOIUrl":"https://doi.org/10.2147/TACG.S245029","url":null,"abstract":"<p><p>Microglia play a critical but poorly understood role in promoting white-matter homeostasis. In this review, we leverage advances in human genetics and mouse models of leukodystrophies to delineate our current knowledge and identify outstanding questions regarding the impact of microglia on central nervous system white matter. We first focus on the role of pathogenic mutations in genes, such as <i>TREM2, TYROBP</i>, and <i>CSF1R,</i> that cause leukodystrophies in which the primary deficit is thought to originate in microglia. We next discuss recent advances in disorders such as adrenoleukodystrophy and Krabbe disease, in which microglia play an increasingly recognized role. We conclude by reviewing the roles of <i>GRN</i> and related genes, such as <i>TMEM106B, PSAP</i>, and <i>SORT1,</i> that affect microglial biology and associate with several types of disease, including multiple leukodystrophies as well as forms of frontotemporal dementia (FTD) presenting with white-matter abnormalities. Taken together, mouse and human data support the notion that loss of microglia-facilitated white-matter homeostasis plays an important role in the development of leukodystrophies and suggest novel mechanisms contributing to FTD.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"195-207"},"PeriodicalIF":3.1,"publicationDate":"2021-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/44/5b/tacg-14-195.PMC8020808.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25583528","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}

{"title":"Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of <i>SERPINA1</i> Variation Spectrum.","authors":"Susana Seixas,&nbsp;Patricia Isabel Marques","doi":"10.2147/TACG.S257511","DOIUrl":"https://doi.org/10.2147/TACG.S257511","url":null,"abstract":"<p><p>Alpha-1-Antitrypsin deficiency (AATD), caused by <i>SERPINA1</i> mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p.Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare <i>SERPINA1</i> variants (>500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss- or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit <i>SERPINA1</i> mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"173-194"},"PeriodicalIF":3.1,"publicationDate":"2021-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6e/4d/tacg-14-173.PMC7997584.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25547023","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}

{"title":"The Effect of Teratozoospermia on Sex Chromosomes in Human Embryos.","authors":"Dalia Mostafa Nayel,&nbsp;Hanan Salah El Din Mahrous,&nbsp;Emad El Din Khalifa,&nbsp;Soha Kholeif,&nbsp;Ghada Mohamed Elhady","doi":"10.2147/TACG.S299349","DOIUrl":"https://doi.org/10.2147/TACG.S299349","url":null,"abstract":"<p><strong>Purpose: </strong>The aim of this study is to evaluate the effect of abnormal semen morphology on the frequency of sex chromosomal abnormalities in embryos obtained by ICSI, which represents the first to be studied in Egyptian population.</p><p><strong>Methods: </strong>Forty-two couples suffering from male infertility due to teratozoospermia were divided into two groups: patients with severe and moderate teratozoospermia (group A and B, respectively). All involved couples were subjected to careful history taking and had a normal clinical examination and karyotype. Females were subjected to hormonal assays, pelvic ultrasound, hysterosalpingography and yielded normal results, while male partners were subjected to computerized semen analysis. Preimplantation genetic diagnosis was performed for all suitably developed embryos including embryo biopsy, fixation of biopsied cells and fluorescent in situ hybridization (FISH) analysis.</p><p><strong>Results: </strong>Couples included in the two groups were found to be homogenous in terms of age of both partners and duration of infertility. Interpretation of FISH results was performed by evaluation of embryos' chromosomal constitution as regards abnormalities in chromosomes X, Y and 18. Twenty-seven embryos (48.2%) were found chromosomally abnormal in group A, while only 14 embryos (25.0%) were found chromosomally abnormal in group B. Aneuploidies involved only sex chromosomes were tripled in group A embryos when compared to their frequency in group B embryos (26.8% and 8.3%, respectively) with statistically significant difference between the two groups (p=0.002). Monosomies were the most common type of aneuploidy and were significantly higher in group A (14.3%) when compared to group B (3.6%) (p=0.047). Embryos with mosaic abnormalities were more common in group A (12.5%) when compared to group B (3.6%), however not statistically significantly different (p= 0.162). A significant difference between the two studied groups as regards the total number of potentially viable chromosomal abnormalities detected and the potentially viable sex chromosomal aneuploidies detected (p<0.001 and p=0.002), respectively.</p><p><strong>Conclusion: </strong>The cases with severe teratozoospermia undergoing ICSI treatment can display a higher rate of sex chromosome aneuploidies in their embryos (threefold) than cases with moderate teratozoospermia.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"125-144"},"PeriodicalIF":3.1,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e9/1c/tacg-14-125.PMC7959001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25498729","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}

{"title":"Identifying Potential Mutations Responsible for Cases of Pulmonary Arterial Hypertension.","authors":"Emmanuel Eroume-A Egom,&nbsp;Roger Moyou-Somo,&nbsp;Jean Louis Essame Oyono,&nbsp;Rene Kamgang","doi":"10.2147/TACG.S260755","DOIUrl":"https://doi.org/10.2147/TACG.S260755","url":null,"abstract":"<p><p>Pulmonary Arterial Hypertension (PAH) is a progressive and devastating disease for which there is an escalating body of genetic and related pathophysiological information on disease pathobiology. Nevertheless, the success to date in identifying susceptibility genes, genetic variants and epigenetic processes has been limited due to PAH clinical multi-faceted variations. A number of germline gene candidates have been proposed but demonstrating consistently the association with PAH has been problematic, at least partly due to the reduced penetrance and variable expressivity. Although the data for bone morphogenetic protein receptor type 2 (BMPR2) and related genes remains undoubtedly the most extensive, recent advanced gene sequencing technologies have facilitated the discovery of further gene candidates with mutations among those with and without familial forms of PAH. An in depth understanding of the multitude of biologic variations associated with PAH may provide novel opportunities for therapeutic intervention in the coming years. This knowledge will irrevocably provide the opportunity for improved patient and family counseling as well as improved PAH diagnosis, risk assessment, and personalized treatment.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"113-124"},"PeriodicalIF":3.1,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/97/d9/tacg-14-113.PMC7958998.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25498728","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}

{"title":"Updates on Genes and Genetic Mechanisms Implicated in Primary Angle-Closure Glaucoma.","authors":"Altaf A Kondkar","doi":"10.2147/TACG.S274884","DOIUrl":"https://doi.org/10.2147/TACG.S274884","url":null,"abstract":"<p><p>Primary angle-closure glaucoma (PACG) is estimated to affect over 30 million people worldwide by 2040 and is highly prevalent in the Asian population. PACG is more severe and carries three times the higher risk of blindness than primary open-angle glaucoma, thus representing a significant public health concern. High heritability and ethnic-specific predisposition to PACG suggest the involvement of genetic factors in disease development. In the recent past, genetic studies have led to the successful identification of several genes and loci associated with PACG across different ethnicities. The precise cellular and molecular roles of these multiple loci in the development and progression of PACG remains to be elucidated. Nonetheless, these studies have significantly increased our understanding of the emerging cellular processes and biological pathways that might provide more significant insights into the disease's genetic etiology and may be valuable for future clinical applications. This review aims to summarize and update the current knowledge of PACG genetics analysis research.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"89-112"},"PeriodicalIF":3.1,"publicationDate":"2021-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b7/06/tacg-14-89.PMC7955727.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25495229","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}

{"title":"Greig Cephalopolysyndactyly (GCPS) Contiguous Gene Syndrome in a Boy with a 14 Mb Deletion in Region 7p13-14 Caused by a Paternal Balanced Insertion (5; 7) [Expression of Concern].","authors":"","doi":"10.2147/TACG.S307411","DOIUrl":"https://doi.org/10.2147/TACG.S307411","url":null,"abstract":"","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"87"},"PeriodicalIF":3.1,"publicationDate":"2021-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f6/d7/tacg-14-87.PMC7943538.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25467108","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}

{"title":"A Novel Frameshift Mutation, Deletion of HBB:c.199_202delAAAG [Codon 66/67 (-AAAG)] in β-Thalassemia Major Patients from the Western Region of Uttar Pradesh, India.","authors":"Waseem Chauhan,&nbsp;Mohammad Afzal,&nbsp;Zeeba Zaka-Ur-Rab,&nbsp;Md Salik Noorani","doi":"10.2147/TACG.S294891","DOIUrl":"https://doi.org/10.2147/TACG.S294891","url":null,"abstract":"<p><strong>Purpose: </strong>Beta thalassemia is one of the most common inherited disorders in India with heterogenous clinical phenotypes from silent carrier to clinically severe ones. Our study aimed to characterize the mutation spectrum in thalassemia patients who are coming to the hospital for follow-up from the western region of Uttar Pradesh India.</p><p><strong>Patients and methods: </strong>For the study, a case series of the retrospective bi-centre study was conducted. The patients from two thalassemia centers in the major hospitals (LLRMC Meerut, and JNMC, Aligarh administered by the Ministry of Health and Family Welfare (MoHFW)) in the Western Uttar Pradesh, India were considered for the study. A total of 77 blood samples were obtained from individuals (both related and unrelated) diagnosed with β-thalassemia after their consent. After DNA extraction, HBB gene amplification, mutation-specific polymerase chain reaction and gene sequencing were carried out to analyze the mutations.</p><p><strong>Results: </strong>In this study, seven different types of mutations were reported for the first time in Western Uttar Pradesh, India. A novel frameshift mutation, deletion of 4 nucleotides Codon 66/67 (-AAAG) in exon 2 region, is reported for the first time. IVS 1-5 (G>C) and Codon 41/42 (-CTTT) are the most frequently reported mutations. The molecular spectrum for these two cases consists of 44 and 42 alleles out of 108 alleles, respectively.</p><p><strong>Conclusion: </strong>A total of 108 β-thalassemia alleles were studied from 46 homozygous and 31 compound heterozygous patients. All the individuals were from 20 districts of the Western Uttar Pradesh, India.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"14 ","pages":"77-85"},"PeriodicalIF":3.1,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/45/46/tacg-14-77.PMC7935337.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25451481","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}