The Experts below are selected from a list of 30219 Experts worldwide ranked by ideXlab platform
Ashok Agarwal - One of the best experts on this subject based on the ideXlab platform.
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evaluation of seminal oxidation reduction potential in Male Infertility
Andrologia, 2021Co-Authors: Manesh Kumar Panner Selvam, Ashok Agarwal, Ralf Henkel, Renata FinelliAbstract:The role of oxidative stress in Male Infertility has been broadly recognised, and the search for a new marker to determine the redox environment in semen has gained considerable interest. Oxidation-reduction potential (ORP) or redox potential, is a measure of the electron transfer from antioxidants to oxidants and provides information on the redox balance. In this review, the benefits of ORP as a new oxidative stress marker, the protocol for its evaluation and the importance of its measurement in the context of Male Infertility are discussed. In association with the standard semen analysis, seminal ORP has been analysed to evaluate semen quality and Male fertility status. However, further studies are required to establish its use in assisted reproductive techniques (ART) practice.
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utility of antioxidants in the treatment of Male Infertility clinical guidelines based on a systematic review and analysis of evidence
The World Journal of Men's Health, 2021Co-Authors: Ashok Agarwal, Ralf Henkel, Renata Finelli, Kristian Leisegang, Ahmad Majzoub, Manesh Kumar Panner SelvamAbstract:It is widely accepted that oxidative stress plays an important role in the pathophysiology of Male Infertility and that antioxidants could have a significant role in the treatment of Male Infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of Male Infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of Male Infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in Male Infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in Male Infertility. The current systematic review on antioxidants and Male Infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic Male Infertility, as well as in cases of altered semen quality.
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Evaluation of seminal Oxidation–Reduction potential in Male Infertility
Andrologia, 2020Co-Authors: Manesh Kumar Panner Selvam, Ashok Agarwal, Renata Finelli, Ralf HenkelAbstract:The role of oxidative stress in Male Infertility has been broadly recognised, and the search for a new marker to determine the redox environment in semen has gained considerable interest. Oxidation-reduction potential (ORP) or redox potential, is a measure of the electron transfer from antioxidants to oxidants and provides information on the redox balance. In this review, the benefits of ORP as a new oxidative stress marker, the protocol for its evaluation and the importance of its measurement in the context of Male Infertility are discussed. In association with the standard semen analysis, seminal ORP has been analysed to evaluate semen quality and Male fertility status. However, further studies are required to establish its use in assisted reproductive techniques (ART) practice.
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role of oxidative stress infection and inflammation in Male Infertility
Andrologia, 2018Co-Authors: Ashok Agarwal, Ralf Henkel, Albert D. Bui, Mohit Rana, Emily Qiu, Hashem AlbunniAbstract:Oxidative stress (OS), defined as an overabundance of reactive oxygen species (ROS) or a deficiency of antioxidants, has been linked to sperm damage and Male Infertility. There are many sources of OS and inflammation including varicocele, tobacco usage, alcohol, obesity/metabolic syndrome, leukocytospermia, sexually transmitted disease (i.e., Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum), bacterial prostatitis, microorganism mutations leading to more OS, and viral infections (i.e., human immunodeficiency virus, hepatitis). This review is focusing on infection and inflammation-mediated OS, the inflammatory markers underlying pathology, clinical significance in Male Infertility, and a brief description of the recommended treatment modalities.
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Update on the proteomics of Male Infertility: A systematic review
Elsevier, 2018Co-Authors: Manesh Kumar Panner Selvam, Ashok AgarwalAbstract:Objective: To assess the role of differentially expressed proteins as a resource for potential biomarker identification of Infertility, as Male Infertility is of rising concern in reproductive medicine and evidence pertaining to its aetiology at a molecular level particularly proteomic as spermatozoa lack transcription and translation. Proteomics is considered as a major field in molecular biology to validate the target proteins in a pathophysiological state. Differential expression analysis of sperm proteins in infertile men and bioinformatics analysis offer information about their involvement in biological pathways. Materials and methods: Literature search was performed on PubMed, Medline, and Science Direct databases using the keywords ‘sperm proteomics’ and ‘Male Infertility’. We also reviewed the relevant cross references of retrieved articles and included them in the review process. Articles written in any language other than English were excluded. Results: Of 575 articles identified, preliminary screening for relevant studies eliminated 293 articles. At the next level of selection, from 282 studies only 80 articles related to Male Infertility condition met the selection criteria and were included in this review. Conclusion: In this molecular era, sperm proteomics has created a platform for enhanced understanding of Male reproductive physiology as a potential tool for identification of novel protein biomarkers related to sperm function in infertile men. Therefore, it is believed that proteomic biomarkers can overcome the gaps in information from conventional semen analysis that are of limited clinical utility. Keywords: Sperm proteomics, Male Infertility, Spermatozoa, Varicocele, Biomarker
Kenneth I. Aston - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
Human Reproduction Update, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Background Human Male Infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'Male Infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human Male Infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human Male Infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
medRxiv, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Abstract Background Human Male Infertility has a notable genetic component, including well established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next generation sequencing technologies, and the absence of clear statements from leaders in the field as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility next generation sequencing studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the extent of evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of July 1st, 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until the 1st of July 2020 for publications in English, using search terms related to “Male Infertility” in combination with the word “genetics” in PubMed. Next, the quality and the extent of all evidence supporting selected genes was assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment, and functional evidence based on gene expression, mutant in vitro cell and in vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, as expressed by the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the ACMG-AMP guidelines and were recorded in spreadsheets for each GDR, which is available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review summarises and curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far past due. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility.
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Harnessing the full potential of reproductive genetics and epigenetics for Male Infertility in the era of "big data".
Fertility and sterility, 2020Co-Authors: Darshan P. Patel, Timothy G. Jenkins, Kenneth I. Aston, Jingtao Guo, Alexander W. Pastuszak, Heidi A. Hanson, James M. HotalingAbstract:The complexity of Male reproductive impairment has hampered characterization of the underlying genetic causes of Male Infertility. However, in the last 20 years, more powerful and affordable tools to interrogate the genetic and epigenetic determinants of Male Infertility have accelerated the number of new discoveries in the characterization of Male Infertility. With this explosion of new data, integration in a systems-based approach-including complete phenotypic information-to Male Infertility is imperative. We briefly review the current understanding of genetic and epigenetic causes of Male Infertility and how findings may be translated into a practical component for the diagnosis and treatment of Male Infertility.
Mario Maggi - One of the best experts on this subject based on the ideXlab platform.
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sexual dysfunction and Male Infertility
Nature Reviews Urology, 2018Co-Authors: Francesco Lotti, Mario MaggiAbstract:Infertility affects up to 12% of all men, and sexual dysfunction occurs frequently in men of reproductive age, causing Infertility in some instances. In infertile men, hypoactive sexual desire and lack of sexual satisfaction are the most prevalent types of sexual dysfunction, ranging from 8.9% to 68.7%. Erectile dysfunction and/or premature ejaculation, evaluated with validated tools, have a prevalence of one in six infertile men, and orgasmic dysfunction has a prevalence of one in ten infertile men. In addition, infertile men can experience a heavy psychological burden. Infertility and its associated psychological concerns can underlie sexual dysfunction. Furthermore, general health perturbations can lead to Male Infertility and/or sexual dysfunction. Erectile dysfunction and Male Infertility are considered proxies for general health, the former underlying cardiovascular disorders and the latter cancerous and noncancerous conditions. The concept that erectile dysfunction in infertile men might be an early marker of poor general health is emerging. Finally, medications used for general health problems can cause sperm abnormalities and sexual dysfunction. The treatment of some causes of Male Infertility might improve semen quality and reverse Infertility-related sexual dysfunction. In infertile men, an investigation of sexual, general, and psychological health status is advisable to improve reproductive problems and general health.
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sexual dysfunction and Male Infertility
Nature Reviews Urology, 2018Co-Authors: Francesco Lotti, Mario MaggiAbstract:In this Review, Lotti and Maggi discuss the correlations between sexual dysfunction and Male Infertility, focusing on the associations between reproductive, sexual, psychological, and general health.
Antoni Rieraescamilla - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
Human Reproduction Update, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Background Human Male Infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'Male Infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human Male Infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human Male Infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
medRxiv, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Abstract Background Human Male Infertility has a notable genetic component, including well established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next generation sequencing technologies, and the absence of clear statements from leaders in the field as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility next generation sequencing studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the extent of evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of July 1st, 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until the 1st of July 2020 for publications in English, using search terms related to “Male Infertility” in combination with the word “genetics” in PubMed. Next, the quality and the extent of all evidence supporting selected genes was assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment, and functional evidence based on gene expression, mutant in vitro cell and in vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, as expressed by the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the ACMG-AMP guidelines and were recorded in spreadsheets for each GDR, which is available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review summarises and curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far past due. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility.
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genetics of Male Infertility
Nature Reviews Urology, 2018Co-Authors: Csilla Krausz, Antoni RieraescamillaAbstract:Male Infertility is a multifactorial pathological condition affecting approximately 7% of the Male population. The genetic landscape of Male Infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to Male Infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of Male Infertility. Despite such efforts, the aetiology of Infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic Infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic Male Infertility.
Albert Salashuetos - One of the best experts on this subject based on the ideXlab platform.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
Human Reproduction Update, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Background Human Male Infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'Male Infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human Male Infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human Male Infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
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a systematic review of the validated monogenic causes of human Male Infertility 2020 update and a discussion of emerging gene disease relationships
medRxiv, 2021Co-Authors: Brendan J Houston, Antoni Rieraescamilla, Margot J Wyrwoll, Albert Salashuetos, Miguel J Xavier, Liina Nagirnaja, Corinna Friedrich, Donald F Conrad, Kenneth I. AstonAbstract:Abstract Background Human Male Infertility has a notable genetic component, including well established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next generation sequencing technologies, and the absence of clear statements from leaders in the field as to what constitutes a validated cause of human Male Infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of Male Infertility next generation sequencing studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known Male Infertility genes and an assessment of the extent of evidence for reported GDRs. Objective and rationale In 2019, the first standardised clinical validity assessment of monogenic causes of Male Infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of July 1st, 2020) for monogenic causes of isolated or syndromic Male Infertility, endocrine disorders or reproductive system abnormalities affecting the Male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of Male Infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. Search methods We performed a literature search according to the PRISMA guidelines up until the 1st of July 2020 for publications in English, using search terms related to “Male Infertility” in combination with the word “genetics” in PubMed. Next, the quality and the extent of all evidence supporting selected genes was assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment, and functional evidence based on gene expression, mutant in vitro cell and in vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, as expressed by the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the ACMG-AMP guidelines and were recorded in spreadsheets for each GDR, which is available at imigc.org. Outcomes The primary outcome of this review was an overview of all known GDRs for monogenic causes of human Male Infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 Infertility phenotypes. Wider implications Our systematic review summarises and curates all currently available evidence to reveal the strength of GDRs in Male Infertility. The existing guidelines for genetic testing in Male Infertility cases are based on studies published 25 years ago, and an update is far past due. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of Male Infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of Male Infertility.