Table of Contents
Overview
Definition and Scope
Neurogenetics is a field that explores the relationship between the genome and the nervous system, encompassing various aspects of genetic mutations, inheritance patterns, and genetic diversity in neurological conditions. It has evolved significantly over the past two to three decades, particularly due to advancements in human genome sequencing, which have facilitated the identification of mutations responsible for neurologic diseases and provided new insights into disease pathophysiology.[3.1] The scope of neurogenetics can be categorized into different approaches. One such approach is instrumental or applied neurogenetics, which utilizes genetic techniques and mutants as tools to analyze structural or functional aspects of the nervous system. This includes the study of mutants that result in homeotic transformations of appendages, among other applications.[4.1] Additionally, neurogenetics encompasses a wide range of neurogenetic disorders, with notable case studies including Alzheimer's, Huntington's, and Parkinson's diseases, highlighting the clinical relevance of genetic research in understanding and treating these conditions.[5.1]Importance in Neuroscience
Neurogenetics plays a pivotal role in advancing the field of neuroscience by elucidating the genetic underpinnings of neurological disorders. This discipline focuses on how genetic variations influence brain structure and function, thereby enhancing our understanding of various neurological conditions. Research in neurogenetics has identified specific genetic factors associated with an increased risk of developing disorders such as Alzheimer’s disease, Parkinson’s disease, and epilepsy. By targeting these genetic factors, researchers aim to develop therapeutic strategies that can modify the underlying genetic contributions to these conditions, ultimately leading to personalized interventions for affected individuals.[8.1] Recent advancements in genome sequencing technologies, particularly the development of next-generation sequencing, have significantly transformed the diagnostic landscape for neurological disorders. Over the past decade, these technologies have shortened the time to diagnosis and increased the number of patients identified as affected by these disorders.[12.1] Whole-exome sequencing (WES) has been extensively utilized in clinical practice, demonstrating a diagnostic yield ranging from 20.4% to 37.5% for neurological disorders in large cohorts, which has been instrumental in elucidating genetic causes in previously undiagnosed patients.[10.1] Moreover, the emergence of long-read sequencing (LRS) and optical genome mapping has provided powerful tools for capturing complex genetic variations, leading to the discovery of novel genes associated with well-characterized neurodegenerative diseases.[14.1] These advancements not only enhance our understanding of the genetic basis of these conditions but also pave the way for improved treatment and prevention strategies. The integration of neurogenetics into clinical practice is significantly advancing personalized clinical care. By leveraging a comprehensive understanding of a patient's genetic profile and medical history, healthcare providers can develop highly tailored treatment programs for individuals, particularly in the context of neurological disorders.[15.1] For instance, advancements in genomics, such as whole genome sequencing and optical genome mapping, allow for a personalized assessment of disease mechanisms, which is crucial for identifying actionable targets in treatment.[19.1] Furthermore, novel technologies, including exome and genome sequencing, as well as mass spectrometry, are increasingly accessible and can guide treatment decisions and monitor the effectiveness of interventions in rare diseases.[18.1] Additionally, methods such as gene expression analysis and CRISPR-Cas technologies facilitate the unraveling of disease mechanisms and the identification of biomarkers for diagnosis and disease activity, thereby enhancing the development of therapeutic strategies.[16.1] This comprehensive approach exemplifies the shift towards preventive, predictive, personalized, and participatory medicine, which is essential for optimizing care in patients with neurological conditions.[16.1]In this section:
History
Early Discoveries in Neurogenetics
Neurogenetics has undergone significant evolution over the past two decades, particularly due to advancements in human genome sequencing. These advancements have facilitated the identification of mutations responsible for various neurologic diseases and have provided new insights into disease pathophysiology.[48.1] The field of neurogenetics, which lies at the intersection of neuroscience and genetics, has a rich history that dates back to the 19th century. Early documentation of hereditary diseases, such as Friedreich's Ataxia and Huntington's Disease, laid the groundwork for understanding the genetic basis of neurological disorders.[49.1] Pivotal discoveries in neurogenetics have marked significant milestones in the understanding of genomic disorders. The integration of advanced cytogenetics, somatic hybrid techniques, and molecular genotyping has refined the mapping of various neurodevelopmental disorders, including fragile X syndrome and Miller-Dieker lissencephaly.[59.1] The 1980s and 1990s saw crucial advancements in molecular biology, including the discovery of microsatellites and improvements in polymerase chain reaction (PCR) techniques, which facilitated genetic mapping and led to significant findings related to several neurological disorders.[60.1] The development of large insert cloning and other physical mapping techniques during the 1990s played a crucial role in the discovery of many disease genes. These techniques revealed that haploinsufficiency or gene duplication could cause overlapping neurological phenotypes, such as those seen in Parkinson's disease and Alzheimer's disease.[62.1] Furthermore, recent studies have implicated rare genetic variants, such as those in the HTRA1 gene, in common diseases, illustrating the importance of examining genetic variations in understanding neurological conditions.[63.1] As research in neurogenetics continues to advance, it holds the potential for developing targeted therapies and improving outcomes for individuals affected by neurological disorders.[61.1] The identification of specific genetic factors associated with conditions like Alzheimer's disease and Parkinson's disease has led to the development of therapeutic strategies aimed at altering the underlying genetic factors contributing to these disorders.[68.1] This ongoing exploration of genetic markers not only enhances the understanding of complex neurological conditions but also guides the development of precision medicine approaches tailored to individual genetic risk patterns.[69.1]Evolution of the Field
The evolution of neurogenetics has been marked by significant milestones that trace its development from the pre-DNA era to contemporary advancements. Initially, the relationship between neurology and heredity was documented in the late 19th century, when several inherited neurological disorders were described, laying the groundwork for what would later be termed neurogenetics.[50.1] This emerging field integrates the disciplines of neurology and genetics, focusing on the correlation between genetic codes and the development and function of the nervous system, including behavioral traits and neurological diseases.[51.1] The advent of genetic testing has revolutionized the diagnosis and management of neurological conditions. It has enabled clinicians to identify the genetic underpinnings of diseases with unprecedented precision, thereby enhancing the understanding of both hereditary and sporadic disorders.[56.1] Genetic testing serves as a rapidly evolving diagnostic tool, allowing for comprehensive diagnoses of hereditary neurological diseases, which has important implications for clinical management.[57.1] Moreover, it facilitates earlier detection and better risk management, leading to the potential for personalized treatments aimed at delaying or preventing disease onset.[58.1] As the field of neurogenetics has advanced, the role of genetic counseling has become increasingly critical. Genetic counseling is essential due to the complexity and variability of neurological conditions, many of which have a strong genetic component influenced by environmental factors.[73.1] Genetic counselors provide personalized guidance to patients and their families, helping them understand the implications of genetic findings related to neurological disorders.[75.1] The demand for genetic counseling has surged in response to the growing number of patients seeking genetic health care, as well as the increasing complexity of cases and available laboratory tests.[76.1] This trend underscores the necessity for pre- and post-test counseling to accompany the expanding array of genetic tests, particularly for presymptomatic assessments.[76.1]Recent Advancements
Technological Innovations
Recent advancements in neurogenetics have been significantly influenced by technological innovations, particularly in genome sequencing technologies. The development of next-generation sequencing (NGS) platforms has revolutionized the ability to determine the genetic etiology of numerous neurological diseases, facilitating the identification of genetic causes that were previously elusive. This technology has led to substantial breakthroughs in understanding both Mendelian and complex neurological disorders, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis.[133.1] Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have emerged as critical tools in clinical practice, with WES achieving a diagnostic yield of 20.4% to 37.5% for neurological disorders in large cohorts.[10.1] However, WGS has proven to be more powerful than WES, particularly in detecting copy number variations (CNVs) and single nucleotide variants (SNVs), which are crucial for understanding complex traits associated with diseases like Charcot–Marie–Tooth disease and spinocerebellar ataxias.[119.1] The application of these sequencing technologies has not only expedited the identification of known disease genes but has also uncovered novel risk factors and pathogenic mutations associated with various neurological conditions.[118.1] Recent advancements in neurogenetics have significantly enhanced our understanding of the genetic factors influencing neuroplasticity and cognitive health. Research has shown that certain genetic variants can affect gene expression, leading to alterations in neuroplasticity. For instance, mutations in the brain-derived neurotrophic factor (BDNF) gene have been linked to impaired plasticity and an increased risk of neurodegenerative disorders.[97.1] Additionally, genome-wide association studies (GWAS) have been crucial in uncovering common genetic variability that contributes to various complex disorders, while whole-exome and whole-genome sequencing have identified rare variants that have substantial effects on both Mendelian and complex diseases.[134.1] These methodologies not only deepen our understanding of neurological disorders but also highlight potential therapeutic avenues for treating brain injuries and neurodegenerative diseases, as researchers have identified specific molecular pathways that facilitate neuroplasticity.[99.1] The integration of these advanced technologies promises to yield further insights and innovations in the field of neurogenetics.Clinical Applications and Implications
Recent advancements in neurogenetics have significantly influenced clinical applications and implications, particularly in the diagnosis and treatment of neurological disorders. The characterization of genetic variations has enabled researchers to design improved diagnostic tools and potential therapies, thereby enhancing personalized medicine approaches. Genetic tests can identify patients at increased risk for neurological disorders, guiding treatment decisions effectively.[100.1] The explosion of new genetic technologies has facilitated the identification of specific genes responsible for various neurological diseases, providing critical insights into their pathophysiology.[101.1] Pathogenic variants in over 1,700 genes have been linked to neurogenetic disorders, making monogenic diseases prime candidates for genetic therapies. However, challenges such as the blood-brain barrier, post-mitotic neurons, and inefficient delivery platforms complicate the application of gene therapies for these conditions.[102.1] Notably, the approval of gene therapies, such as those for cerebral adrenoleukodystrophy, marks a significant milestone in the treatment landscape for neurogenetic disorders.[103.1] Recent studies utilizing large datasets have provided significant insights into the correlations between pathogenic gene variations and clinical phenotypes in individuals with neurogenetic disorders, which may inform potential therapeutic interventions.[104.1] The field of clinical neurogenetics has evolved rapidly, with indications for genetic testing no longer relying solely on family history. This shift is crucial, as family history can often be misleading due to factors such as misdiagnosis, misattribution of symptoms, incomplete and age-related penetrance, or the presence of de novo genetic variants.[114.1] Advances in neurogenetics have also led to practical applications, allowing for rapid diagnosis through non-invasive methods such as blood and body fluid analysis to extract DNA. This capability enables presymptomatic diagnoses via genetic screening and biomarkers, which can guide life-saving disease-modifying therapies or enzyme replacement strategies.[108.1] Patient advocacy organizations play a crucial role in translating advancements in neurogenetics into practical support for patients and their families. These organizations provide education, resources, and advocacy for the development of gene therapies, enhancing patient experiences and promoting health literacy.[107.1] As the field continues to evolve, the integration of neurogenetic findings into clinical practice is expected to improve patient outcomes through more effective and targeted therapies.[112.1]In this section:
Genetic Basis Of Neurological Disorders
Common Genetic Disorders
Recent advancements in genetic testing have significantly influenced the diagnosis and understanding of common neurological disorders, particularly Alzheimer's disease (AD) and other neurodegenerative conditions. The identification of rare genetic mutations associated with early-onset AD, such as those on chromosomes 1 (PSEN2), 14 (PSEN1), and 21 (APP), has enabled predictive genetic testing for families with a known or suspected mutation, despite these variants accounting for a small proportion of overall AD cases.[152.1] The integration of genetic testing into the diagnostic pathway for dementia can potentially reduce the time required to ascertain the underlying cause of the condition, thereby enhancing the diagnostic process.[153.1] Genetic testing not only aids in establishing a definitive diagnosis but also improves familial understanding of the disease and offers at-risk relatives the option for predictive testing.[151.1] Moreover, technological advancements, particularly in next-generation DNA sequencing, have facilitated the rapid identification of causative genes associated with various neurological disorders. This progress allows for more precise diagnoses and suggests that genetic testing should be incorporated earlier in the diagnostic process.[155.1] As the number of identified pathogenic variants increases, genetic testing has also improved the ability to provide recurrence risk information to family members and, in some instances, determine eligibility for clinical trials.[156.1] Ultimately, the detailed genetic and molecular characterizations achieved through these advancements may lead to personalized treatment options and improved therapeutic strategies for patients suffering from common neurological disorders.[157.1]In this section:
Neurogenomics And Precision Medicine
Personalized Treatment Approaches
Personalized treatment approaches in neurogenetics are increasingly influenced by advancements in precision medicine, particularly through the application of neural stem cells, induced pluripotent stem cells (iPSCs), genetic profiling, and pharmacogenetics, especially in the contexts of Alzheimer's disease and schizophrenia.[186.1] These approaches aim to enhance our understanding of the genetic architecture of neurodegenerative diseases, which is essential for developing novel disease-modifying therapies.[185.1] Furthermore, pharmacogenetic studies have provided valuable insights into the variability of drug responses among individuals, highlighting their implications for patient management in clinical practice.[190.1] By evaluating current achievements alongside existing challenges, the integration of these personalized approaches is crucial for improving patient outcomes in neurology.[185.1] Pharmacogenetics is increasingly recognized as a vital component in the personalized treatment of neurological disorders, as it provides insights into the variability of drug responses among individuals.[190.1] This field is expected to become a standard consideration in pharmaceutical use, yet there remains a significant gap in the availability of relevant information for practicing physicians.[191.1] Despite the promising results from pharmacogenetic studies, the integration of these insights into clinical practice faces several barriers. Key challenges include the fragmentation of healthcare systems, which complicates the delivery of consistent care over a patient's lifetime, and the prevailing focus of healthcare delivery systems on treating illness rather than preventing disease.[194.1] Additionally, the lack of robust clinical practice guidelines and algorithms further hinders the translation of pharmacogenetic findings into everyday clinical settings.[193.1] To effectively implement personalized treatment approaches, it is essential that these guidelines are not only comprehensive and up-to-date but also flexible enough to adapt to new research developments.[193.1] The integration of genetic profiling into the management of neurodegenerative diseases (NDDs) presents significant challenges, particularly in diverse patient populations. Key hurdles include determining patient eligibility for genetic testing, ensuring the appropriate use of diagnostic tools, and effectively detecting and monitoring treatment side effects.[200.1] Additionally, resource limitations such as financial constraints, access to specialized care, and insufficient caregiver support further complicate the management of these disorders.[201.1] These complexities highlight the necessity for a collaborative, multidisciplinary approach to care that addresses the social, economic, and ethical implications of neurodegenerative diseases.[201.1] Traditional classifications of NDDs, which have relied on clinical symptoms and post-mortem findings, often fail to capture the intricate molecular, genetic, and temporal dynamics involved, underscoring the need for more personalized treatment strategies.[202.1] As research continues to uncover the genetic underpinnings of neurodegenerative disorders, the development of targeted therapies is becoming increasingly feasible. For instance, gene therapies aimed at correcting disease-causing mutations are being explored, although challenges such as the blood-brain barrier and delivery mechanisms remain significant obstacles.[205.1] Overall, the evolution of personalized treatment approaches in neurogenetics holds promise for improving outcomes in patients with neurological disorders, contingent upon overcoming existing barriers and enhancing the integration of genetic insights into clinical practice.Future Directions in Neurogenomics
Recent advancements in neurogenetic testing are paving the way for a new era of personalized medicine in neurology. These developments leverage genetic insights to facilitate more precise, effective, and individualized care for patients with neurological disorders, ultimately enhancing their quality of life.[218.1] The genotype-first diagnostic approach has gained traction due to the increasing availability of genetic technologies, such as next-generation sequencing (NGS) and DNA microarrays, which provide greater opportunities for diagnosing patients and their family members.[219.1] Moreover, the rapid progress in sequencing technology has significantly improved diagnostic capabilities for rare neurological diseases, which can greatly influence clinical management and the development of personalized treatments.[221.1] As these technologies advance, it is crucial for insights from researchers and geneticists to inform clinical practice, particularly as methods for modifying gene expression and editing genes or the epigenome transition into clinical settings.[220.1] In the context of specific neurological disorders, there is growing evidence linking genetic variations to conditions such as schizophrenia and Alzheimer's disease (AD). Both disorders exhibit substantial genetic components, with schizophrenia having an estimated heritability of approximately 80% and AD ranging from 60% to 80%.[224.1] Recent genome-wide association studies (GWAS) have identified numerous loci associated with these conditions, primarily located outside protein-coding regions, suggesting they may influence gene transcription.[226.1] Furthermore, polygenic risk scores (PRSs) for schizophrenia and AD indicate some genetic predisposition, although findings remain inconsistent across studies.[225.1] The genetic correlations between schizophrenia and AD, while weak, suggest a complex interplay of genetic factors that may inform our understanding of the underlying mechanisms of these disorders.[225.1] As research continues to uncover the genetic underpinnings of neurogenetic disorders, the integration of these insights into clinical practice will be essential for advancing precision medicine in neurology.In this section:
Ethical Considerations
Genetic Testing and Patient Privacy
Genetic testing, particularly in the context of neurogenetics, raises significant ethical considerations regarding patient privacy and informed consent. The complexities surrounding informed consent are particularly pronounced when testing minors, as both parental consent and the child's assent are required. The National Society of Genetic Counselors has advocated for deferring predictive genetic testing of minors for adult-onset conditions, emphasizing the importance of allowing individuals to make informed choices as adults based on their circumstances and beliefs.[236.1] Similarly, the American College of Medical Genetics and Genomics, in collaboration with the American Academy of Pediatrics, has reaffirmed the necessity of deferring such testing until adulthood.[236.1] Informed consent in genetic testing is not merely a procedural formality; it is a critical component that ensures patient autonomy and addresses the potential implications of genetic findings. The American Society of Human Genetics and ACMG recommend that the informed consent process should include an assessment of the benefits and harms of the test, an evaluation of the child's decision-making capacity, and advocacy for the child's interests.[238.1] This is particularly important given that genetic findings can lead to incidental discoveries that may not directly correlate with health outcomes, thereby complicating the interpretation of results.[238.1] Legal frameworks governing informed consent in neurogenetic testing are derived from a complex intersection of state and federal case law, statutes, and regulations, including relevant federal anti-discrimination legislation such as the Americans with Disabilities Act (ADA) and the Genetic Information Nondiscrimination Act (GINA).[239.1] Informed consent is an integral part of the genomics research endeavor, as sequencing a person’s genome can have implications for identity and privacy.[241.1] The informed consent process is crucial for maintaining the autonomy of research participants, and researchers should consider the information that participants need to understand the risks and potential benefits of their involvement in studies.[241.1] The National Human Genome Research Institute (NHGRI) has developed resources to assist researchers in creating effective informed consent processes, which include sample language for consent forms and guidance on the required elements for informed consent, particularly in the context of genomic data sharing.[241.1] The ethical responsibilities of healthcare providers are further complicated by the need for transparency regarding the collection, use, and sharing of genetic data. Key recommendations for best practices in genetic data management include ensuring detailed transparency about data handling, obtaining separate consent for data transfer to third parties, and providing educational resources about genetic testing.[260.1] Additionally, there is a growing recognition of the need for robust legal protections to safeguard genetic information, particularly as advancements in genetic testing continue to evolve.[261.1] This intersection of biotechnology and privacy law underscores the urgency of establishing comprehensive legal frameworks to protect individuals' genetic data and uphold ethical standards in neurogenetics.Implications of Genetic Research
The implications of genetic research in neurogenetics are profound and multifaceted, raising significant ethical questions that must be addressed as the field advances. The ability to manipulate or alter genetic information introduces potential unforeseen consequences, particularly concerning consent and the rights of vulnerable populations.[234.1] Ethical considerations have been central to discussions surrounding neurogenetic issues, especially as rapid advancements in diagnostic and therapeutic genetic technologies present novel dilemmas.[231.1] One critical area of concern is the application of predictive genetic testing, which allows asymptomatic relatives to assess their risk for neurogenetic conditions. Professional guidelines emphasize the importance of patient autonomy and informed, voluntary decision-making in this context.[230.1] However, ethical issues arise when considering the age of the patient, particularly minors, as organizations like the National Society of Genetic Counselors advocate for deferring predictive genetic testing for adult-onset conditions until individuals can make informed choices as adults.[229.1] Moreover, the complexity of genetic testing and the various types of results can create ethical challenges for clinicians. Neurologists must navigate the principles of beneficence and nonmaleficence while ensuring that patients are adequately counseled to make informed decisions about their care.[235.1] This balance is crucial in fostering shared decision-making and maintaining the fiduciary responsibilities of healthcare providers. As genetic research progresses, particularly with the advent of technologies like CRISPR, the ethical frameworks governing informed consent and the potential for unforeseen consequences must evolve. The increasing prevalence of genome-editing trials necessitates a re-evaluation of the informed consent process to ensure that participants are fully aware of the risks and benefits involved.[244.1] Furthermore, the ethical considerations surrounding gene editing raise profound questions about our moral responsibilities towards future generations and the potential alteration of human nature.[246.1]Challenges And Future Perspectives
Current Limitations in Research
The timely diagnosis of neurogenetic conditions presents significant challenges, particularly in identifying dynamic mutations, which are characterized by an increased number of repetitions of specific trinucleotides. These mutations are associated with various neurological and neuromuscular disorders, complicating the development of effective therapies due to their intergenerational variability and the complexities of their genetic underpinnings.[282.1] Pathogenic variants in over 1,700 genes can cause neurogenetic disorders, making monogenic diseases ideal targets for genetic therapies. However, significant challenges exist in the development of these therapies due to the blood-brain barrier (BBB), the post-mitotic nature of neurons, and inefficient delivery platforms.[283.1] Following the approval of nusinersen in 2016, the field has seen rapid advancements in gene therapies for neurogenetic disorders, including the development of new delivery vehicles such as BBB-crossing capsids, engineered viral-like proteins, and lipid nanoparticles (LNPs).[285.1] Despite these advancements, there remains a critical need for innovation in regulatory and commercial pathways to facilitate the translation of these therapies and to reduce the time and cost associated with their development.[283.1] The interpretation of rare genetic variants associated with neurodevelopmental disorders presents significant challenges for healthcare professionals, particularly due to the presence of variants of uncertain significance (VUS).[286.1] This complexity complicates clinical decision-making, as professionals must navigate the intricacies of variant pathogenicity, often relying on gene family information for accurate classification.[288.1] Whole genome sequencing (WGS) remains the gold standard for discovering rare variants, as it allows for comprehensive analysis of genomic modifications, including those in difficult regions of the genome.[287.1] Given the labor-intensive nature of interpreting these variants, automating the processes of variant annotation and prioritization is essential to streamline diagnostics and reduce the burden on clinicians.[289.1] Despite these challenges, advancements in genetic technologies have the potential to improve diagnosis and treatment outcomes for patients with neurogenetic disorders. For instance, the approval of nusinersen in 2016 marked a significant milestone in the development of gene therapies, leading to rapid advancements in delivery vehicles and therapeutic strategies.[285.1] As the understanding of pathomechanisms deepens, there is hope for the development of specific therapeutic options for rare neurogenetic diseases, which constitute a significant portion of genetic disorders affecting the nervous system.[290.1]Potential for Future Discoveries
The potential for future discoveries in neurogenetics is significant, particularly as advancements in genetic testing and gene editing technologies continue to evolve. One of the primary challenges in this field is the nature of mutation types frequently encountered in neurodegenerative diseases, such as dynamic mutations that underlie conditions like Huntington disease and fragile-X mental retardation.[265.1] Despite these challenges, there is optimism regarding the translation of genetic information into revolutionary therapies, although the pace of therapeutic development has been slower than anticipated.[266.1] Recent studies have demonstrated the significance of investigating rare genetic variants, particularly those in the HTRA1 gene, which have been associated with the occurrence of white matter hyperintensities in the general population.[267.1] These findings underscore the importance of utilizing large public datasets to enhance our understanding of genetic contributions to common diseases, as they reveal that heterozygous variants within autosomal recessive genes are not always benign, a concept predicted by Vogel nearly 40 years ago.[267.1] Additionally, the ongoing discourse surrounding gene editing technologies has led to calls for intensive basic and preclinical research, which is essential to ensure that such research proceeds under appropriate legal and ethical guidelines.[268.1] The organizing committee at a recent summit emphasized the need for global engagement and discussion regarding gene editing, highlighting that many promising applications are focused on altering genetic sequences in somatic cells, while also addressing the ethical, legal, and scientific questions surrounding germline editing that remain unresolved.[268.1] As gene editing technologies become more accessible, ethical considerations will play a crucial role in shaping the future of neurogenetics. The potential for heritable genome editing raises significant ethical, scientific, and social challenges that must be addressed to prevent unintended generational changes.[269.1] The debate surrounding germline editing has intensified, especially given the concerns about informed consent and equitable access to these technologies.[270.1] The establishment of the Human Genome Editing Initiative by the National Academy of Science and the National Academy of Medicine in 2015 marked a significant step towards creating informed decision-making processes regarding germline editing experiments, particularly in response to ethical concerns raised by advancements in gene editing technologies.[271.1] This initiative has organized three international summits that convene experts to discuss both the technological advances in the field and the necessary ethical frameworks for responsible research practices.[271.1] Concurrently, the role of genetic testing in neurologic clinical practice has seen a dramatic increase in recent years, driven by research on the genetic causes of neurologic diseases and the enhanced availability of genetic sequencing technology.[275.1] As a result, it is essential to integrate genetic evaluations into clinical management, particularly for individuals with genetic developmental disorders such as global developmental delay/intellectual disability (GDD/ID), autism spectrum disorder (ASD), and cerebral palsy (CP).[274.1] Offering genetic evaluation to these individuals can lead to numerous benefits, including improved medical management, reproductive counseling, access to clinical trials, and the facilitation of family testing.[274.1]References
[3] Introduction to Neurogenetics - The American Journal of Medicine — INTRODUCTION Neurogenetics has evolved considerably over the past 20 years. Advancements in human genome sequencing have led to the identification of mutations that cause neurologic disease and to fundamentally new insights into disease pathophysiology. These advances along with technologi-
[4] Introduction to Neurogenetics | SpringerLink — Neurogenetics deals with the relations between the genome and the nervous system. The term neurogenetics is used in at least three different ways:. Instrumental or applied neurogenetics uses mutants or genetic techniques as tools for analyzing structural or functional aspects of the nervous system. Examples of this are the use of mutants that lead to homeotic transformations of appendages or
[5] 3 months online training on neurogenetics — Introduction to neurogenetics: genetic mutations, inheritance patterns, and genetic diversity in neurological conditions; Overview of neurogenetic disorders, with case studies in Alzheimer's, Huntington's, and Parkinson's Diseases; 2. Genetics of Parkinson's Disease.
[8] Exploring the Relationship Between Genetic and Neurological Factors — Research has identified specific genetic factors that are associated with an increased risk of developing certain neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and epilepsy. By targeting specific genes that are linked to these disorders, researchers aim to develop therapeutic strategies that can alter the underlying genetic factors contributing to the development and progression of neurological conditions. By identifying these genetic risk factors, researchers and healthcare professionals can better understand the underlying mechanisms of neurological disorders and develop personalized interventions for individuals affected by these conditions. The study and understanding of genetic mutations and their impact on neurological factors is crucial in advancing our knowledge of brain function and developing strategies for prevention and treatment of neurological disorders.
[10] Diagnostic yield and treatment impact of whole‐genome sequencing in ... — To date, whole-exome sequencing has been used extensively in clinical practice to elucidate genetic causes in previously undiagnosed patients using historical approaches, with a higher diagnostic yield of 20.4% to 37.5% for neurological disorders in large cohorts. 3, 6, 7 Nevertheless, WGS has proven more powerful than whole-exome sequencing
[12] Current Advances and Challenges in Gene Therapies for Neurologic Disorders — The past decade has led to major advances in diagnostics, including the availability of next-generation sequencing. 2 This has shortened the time to diagnosis and increased the numbers of patients known to be affected by these disorders. Furthermore, several diseases have now been added to newborn screening (NBS) panels.
[14] Exploration of Neurodegenerative Diseases Using Long‐Read Sequencing ... — Recently, long-read sequencing (LRS) and optical genome mapping technologies have emerged as powerful tools, offering the ability to capture more complex genetic variations. These technologies have already led to the discovery of novel genes responsible for well-characterized neurodegenerative diseases (ND), enhancing the understanding of the
[15] Neurogenetics > Fact Sheets - Yale Medicine — Neurogenetics is also helping to advance the concept of personalized clinical care. With a comprehensive understanding of a patient's genetic profile and medical history, physicians can create highly tailored treatment programs for each patient. For example, a cancer patient can now receive genome analysis of the specific mutations within a
[16] Personalized medicine for rare neurogenetic disorders: can we make it ... — Using methods such as gene expression, CRISPR–Cas technologies, and genetic engineering of cell models and model organisms (“functional genetics”), it is possible to unravel disease mechanisms, identify biomarkers for diagnosis and disease activity, and develop therapeutic strategies in a so-called translational metabolism model (van Karnebeek et al. The PKU story is a fine example of “preventive, predictive, personalized, and participatory” medicine (P4 medicine; Fig. 2), a model increasingly applied over the past five decades to provide optimal care for IMD patients (Hood et al. This resulted in the so-called lysine reduction therapy (LRT), a dietary treatment in combination with arginine supplementation, leading to an improvement in epilepsy control and psychomotor development in treated patients (P4: personalized) (Coughlin et al.
[18] Editorial: Developing personalized treatment in neurodegenerative ... — Editorial: Developing personalized treatment in neurodegenerative disorders: role of genomics and novel technologies in identifying actionable targets and developing interventions in rare-diseases - PMC Editorial: Developing personalized treatment in neurodegenerative disorders: role of genomics and novel technologies in identifying actionable targets and developing interventions in rare-diseases Furthermore, novel technologies, be it genetic, such as exome and genome sequencing, that are explored in detail in other recent Research Topic (Mao et al., 2023), or other, such as mass spectroscopy, are available and accessible and can be used to guide us in our decision to treat, as well as to follow-up on the effectiveness of the intervention.
[19] Developing Personalized Treatment in Neurodegenerative Disorders: Role ... — Simultaneously, advances in genomics (whole genome sequencing, optical genome mapping) have enabled us to personalized assess disease mechanisms. This re-examination of what is actionable in neurological and rare diseases should be our collective first step towards developing personalized treatment.
[48] Introduction to Neurogenetics - The American Journal of Medicine — Neurogenetics has evolved considerably over the past 20 years. Advancements in human genome sequencing have led to the identification of mutations that cause neurologic disease and to fundamentally new insights into disease pathophysiology. ... . 5-12 In the following, we will review the key cellular processes that are disrupted in neurogenetic
[49] Tracing the Threads of Neurogenetics: From Inherited Disorders to ... — Neurogenetics stands at the intersection of neuroscience and genetics, unraveling how genes influence the nervous system's development and disorders. This blog post delves into the field's rich history, from 19th-century documentation of hereditary diseases like Friedreich's Ataxia and Huntington's Disease to transformative 20th-century advancements led by pioneers like Seymour Benzer.
[50] A journey through the history of Neurogenetics - Semantic Scholar — The main historical hallmarks of Neurogenetics, from the pre-DNA era to the present, and the future directions of the field are summarized. ABSTRACT Since the late 19th century, when several inherited neurological disorders were described, the close relationship between Neurology and heredity were well documented by several authors in a pre-genetic era. The term Neurogenetics came to integrate
[51] A journey through the history of Neurogenetics - PubMed — The term Neurogenetics came to integrate two large sciences and clinical practices: Neurology and Genetics. Neurogenetics is the emerging field that studies the correlation between genetic code and the development and function of the nervous system, including behavioral traits, personality and neurological diseases.
[56] How Genetics Impact Neurological Conditions - Maryland Neuromuscular Center — Genetic testing has revolutionized the diagnosis and management of neurological conditions, enabling clinicians to pinpoint the genetic underpinnings of diseases with unprecedented precision. It offers a deeper understanding of hereditary and sporadic disorders, guiding both diagnosis and treatment. Key Benefits of Genetic Testing in Neurological Conditions
[57] PDF — • Genetic testing is rapidly evolving as a diagnostic tool. • This allows comprehensive diagnosis of hereditary neurological diseases, with important implications for clinical manage-ment. • Pre-symptomatic diagnosis should be done with care. • Incidental findings arise from genome-wide analysis, and a strategy is needed for dealing
[58] Genetics in Neurological Diseases: Key Insights & Impact — Genetic testing identifies mutations. They are typically associated with hereditary factors. It allows for earlier detection and better risk management. This leads to the possibility of personalized treatments to delay or prevent disease onset. Genome Analysis and Its Impact on Neurological Disease Research
[59] Advancing Neurogenetics: Pioneering the Future of Brain Research — These pivotal discoveries marked the beginning of exploring genomic disorders in neurobiology and beyond . Similar amalgamations of advanced cytogenetics, somatic hybrid techniques, and molecular genotyping played a vital role in refining the maps of various neurodevelopmental disorders, including fragile X syndrome, Miller-Dieker lissencephaly
[60] Tracing the Threads of Neurogenetics: From Inherited Disorders to ... — His contributions are often regarded as pivotal in defining neurogenetics as a distinct field. Advancements in Molecular Biology (1980s-1990s) ... The discovery of microsatellites and advancements in polymerase chain reaction (PCR) techniques during the 1990s facilitated genetic mapping and led to significant findings related to several
[61] Advancements in Neurogenetics: Identifying Disease-Linked Genes - iCliniq — As research in neurogenetics continues to evolve, it holds the potential to provide targeted therapies and improved outcomes for individuals affected by these conditions. The promising discoveries made in this field offer hope for a future where neurological disorders can be better managed and potentially cured.
[62] Neurogenetics: Advancing the "Next-Generation" of Brain Research — The development of large insert cloning and other physical mapping techniques (Burke et al., 1987; Schwartz and Cantor, 1984), as part of the framework for sequencing the human genome, played a crucial role in facilitating the discovery of many disease genes during the nineties. Haploinsufficiency or loss as well as doubling of several genes seems to cause overlapping neurological phenotypes including Parkinson disease, Alzheimer disease, the case of peripheral myelin protein 22 in neuropathies, MeCP2 in Rett syndrome, and MeCP2 duplication disorders, and the example of gain-of-function and loss-of-function mutations in neuronal ion channels causing epilepsy and other neurological deficits (Amir et al., 1999; Catterall et al., 2008; Van Esch et al., 2005; Zhang et al., 2010).
[63] The Neurogenetics Collection: emerging themes and future considerations ... — In a recent issue of Brain, two groups implicated rare variants in the HTRA1 gene in the occurrence of white matter hyperintensities in the general population.16,17 Together, these studies show the value of examining rare variants as a cause of common diseases.18 They also illustrate that heterozygous variants located within autosomal recessive genes are not always benign, a disease pattern predicted by Vogel nearly 40 years ago.19 Aside from the clinical importance of their findings, both papers illustrate a growing trend in genetics, namely the use of large public datasets to support their work.
[68] Genetic and neurological factors have a profound impact on the ... — Research has identified specific genetic factors that are associated with an increased risk of developing certain neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and epilepsy. By targeting specific genes that are linked to these disorders, researchers aim to develop therapeutic strategies that can alter the underlying genetic factors contributing to the development and progression of neurological conditions. By identifying these genetic risk factors, researchers and healthcare professionals can better understand the underlying mechanisms of neurological disorders and develop personalized interventions for individuals affected by these conditions. The study and understanding of genetic mutations and their impact on neurological factors is crucial in advancing our knowledge of brain function and developing strategies for prevention and treatment of neurological disorders.
[69] How Genetics Impact Neurological Conditions - Maryland Neuromuscular Center — Genetic mutations and variations play a pivotal role in the onset and progression of several neurological conditions, such as Alzheimer’s disease and Parkinson’s disease. The continuous exploration of genetic markers not only deepens our understanding of complex neurological conditions but also guides the development of precision medicine approaches tailored to individual patterns of genetic risk. Understanding the distinction between inherited and sporadic neurological conditions is essential for comprehending the genetic and environmental influences on these disorders. Family history provides a critical foundation for assessing genetic risks in neurological conditions, serving as a key tool to guide early diagnosis and proactive management. Early Detection and Prevention: A strong family history of neurological conditions, such as Parkinson’s disease or Huntington’s disease, can highlight at-risk individuals, allowing for early intervention.
[73] Discover the Role and Importance of Genetic Counselors in Modern Healthcare — The Importance of Genetic Counseling in Neurogenetics. Genetic counseling is especially important in neurogenetics due to the complexity and variability of these conditions. Many neurological disorders have a strong genetic component, but their development and progression can also be influenced by environmental factors and other non-genetic
[75] Genetic Counseling - Northwestern Medicine — Genetic counselors are professionals who have specialized education to provide personalized guidance as patients make decisions about their genetic health. ... The Role of a Genetic Counselor . ... identifies who in the family is at risk for an inherited neurogenetics condition, and provides information about genetic testing and family planning
[76] The role of the genetic counsellor: a systematic review of research ... — Meiser et al10 undertook a systematic review of studies that involved analysis of actual genetic counselling sessions by genetic health-care providers, including genetic counsellors. Authors stated that there was a need for genetic counsellors to be utilised to provide care because the number of patients seeking genetic health care was growing rapidly and the numbers of available medical geneticists could not cope with the demand;16 the increased demand for genetic counsellors was also related to increase in the complexity of cases and the number of laboratory test that were available, for which informed consent was necessary.16 Related to this point, Kromberg et al17 suggested that the role of the genetic counsellor would expand further, as pre- and post-test counselling was essential to accompany the increasing number of tests available, particularly for presymptomatic tests.
[97] Understanding Neurogenetic Research and its Impact on the Brain — Research in neurogenetics has revealed that certain genetic variants can affect the expression of these genes, leading to alterations in neuroplasticity. For example, a mutation in a gene called BDNF (brain-derived neurotrophic factor) has been associated with impaired plasticity and an increased risk of neurodegenerative disorders such as
[99] Top 6 Neuroscience Breakthroughs of 2024 - praguebrainsgroup.com — Enhanced Brain-Computer Interfaces Researchers anticipate that such interfaces will soon facilitate cognitive enhancement and restore sensory experiences, such as vision and hearing, in patients with sensory impairments. The integration of advanced sensors and neural interfaces has been key to this development, offering hope for more natural and effective prosthetic solutions. Researchers have identified specific molecular pathways that facilitate neuroplasticity, opening up potential therapeutic avenues for treating brain injuries and neurodegenerative diseases. It also highlights the potential for developing interventions that promote brain health and cognitive resilience throughout life. Sleep science has benefited from neuroscientific advancements in 2024, with researchers uncovering new connections between sleep patterns and cognitive health.
[100] Neurogenetics | Journal of Neurological Research And Therapy — By studying the genetic variations that contribute to these conditions, researchers are able to design better diagnostic tools and potential therapies. Moreover, neurogenetics has implications for personalized medicine, as genetic tests can help identify patients at increased risk for neurological disorders and guide treatment decisions. For
[101] Introduction to Neurogenetics - The American Journal of Medicine — Genetic variation can directly cause or increase susceptibility to neurologic diseases. An explosion of new genetic technologies has enabled the characterization of specific genes responsible for many neurologic diseases and has provided fundamentally new insight into their pathophysiology. These advancements, along with recent breakthroughs in gene therapy, are beginning to result in the
[102] Gene therapies for neurogenetic disorders - Cell Press — Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders
[103] Genetic testing in adults with neurologic disorders: Indications ... — Keywords: neurogenetics, genetic testing, adult neurology, clinical impact. ... Gene therapy for boys with cerebral adrenoleukodystrophy was FDA approved in 2022 and EMA approved in 2021, ... Finally, neuropathy can be a symptom in >200 multi-system genetic disorders, so multisystem involvement is an additional indication for genetic testing.
[104] Mechanisms underlying phenotypic variation in neurogenetic disorders ... — Studies in large data sets are providing important insights into the correlations between pathogenic gene variation and clinical phenotypes in people with neurogenetic disorders. These analyses
[107] 'Advocacy groups are the connectors': Experiences and contributions of ... — ‘Advocacy groups are the connectors’: Experiences and contributions of rare disease patient organization leaders in advanced neurotherapeutics - PMC ‘Advocacy groups are the connectors’: Experiences and contributions of rare disease patient organization leaders in advanced neurotherapeutics Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. To maximize heterogeneity and characterize the spectrum of perspectives, all partner organizations listed on the Rare Voices Australia (RVA) website; large RDPO alliances throughout Europe and North America; and other RDPOs known to researchers through established health partnerships were invited to participate. the expectations, hopes and fears of rare disease patients on large‐scale data and biomaterial sharing for genomics research. Integrating patient perspectives in medical decision‐making: a qualitative interview study examining potentials within the rare disease information exchange process in practice.
[108] Neurogenetics - an overview | ScienceDirect Topics — Advances in the field of neurogenetics have practical applications in rapid diagnosis on blood and body fluids to extract DNA, obviating the need for invasive investigations. The ability to obtain a presymptomatic diagnosis through genetic screening and biomarkers can be a guide to life-saving disease-modifying therapy or enzyme replacement
[112] Neurogenetics - Institute of Clinical Medicine - UiO — Ultimately, our research strives to significantly enhance patient care and outcomes, ensuring more effective and targeted therapies for neurological conditions. Omics-data in web application In order to look up data for all genes, generate different plots or replicate findings, we provide access to all our omics-data used in our studies through
[114] Genetic testing in adults with neurologic disorders: Indications ... — Clinical neurogenetics has evolved rapidly. Indications for testing no longer rely entirely on family history, which can be misleading due to misdiagnosis or misattribution of symptoms, incomplete and age-related penetrance, or de novo genetic variants ("genetic" is not synonymous with "inherited"). The approach to genetic testing has
[118] Next generation sequencing for neurological diseases: new hope or new ... — Over the past year huge advances have been made in our ability to determine the genetic aetiology of many neurological diseases through the utilisation of next generation sequencing platforms. This technology is, on a daily basis, providing new breakthroughs in neurological disease. The aim of this …
[119] Next-Generation Sequencing Technologies and Neurogenetic Diseases — In this review, we compare the differences between several sequencing methods and review NGS -identified genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease (CMT), spinocerebellar ataxias (SCA), epilepsy, and multiple sclerosis (MS), introducing novel pathogenic mutations recently discovered. Accordingly, WGS is currently considered superior to WES in the detection of CNVs and SNVs. Familial WGS provides information on the genetic basis of polyneuropathies with complex traits, such as Parkinson’s disease, ALS, and Alzheimer’s disease , with the rate of genome coverage significantly increased compared with WES. 123.McMillan H.J., Schwartzentruber J., Smith A., Lee S., Chakraborty P., Bulman D.E., Beaulieu C.L., Majewski J., Boycott K.M., Geraghty M.T. Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease.
[133] Next generation sequencing in understanding complex neurological ... — Next generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer's disease, Parkinson's disease
[134] Next generation sequencing techniques in neurological diseases ... — Genome-wide association studies (GWAS) have been essential to uncover common variability contributing to various complex disorders. Whole-exome and whole-genome sequencing have identified rare variants causing or imparting large effects both on Mendelian as well as on complex diseases.
[151] Genetic counseling and testing for Alzheimer disease: Joint practice ... — The use of genetic testing for diagnostic purposes in early-onset autosomal dominant AD has long been debated by clinicians in the dementia field. 50, 86, 87 Although mutations are rare and testing may reveal variants of unknown significance, genetic testing may result in definitive diagnosis, improve understanding for the family, and allow at-risk relatives to have the option of predictive
[152] Implications of Emerging Uses of Genetic Testing for Alzheimer's ... — Predictive and Susceptibility Testing. In the 1990s, rare genetic mutations causing early-onset AD were identified on chromosomes 1 (PSEN2), 14 (PSEN1), and 21 (APP) ().These pathogenic variants account for a very small proportion of AD cases, but allow for predictive genetic testing if there is a known or suspected mutation within a given family ().
[153] Genetic testing in dementia-A medical genetics perspective — Conclusions: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.
[155] Current scenario of the genetic testing for rare neurological disorders ... — The advances can allow a rapid identification of causative genes and a more precise genetic diagnosis of many neurological disorders. Thus, genetic testing should be considered earlier in the diagnostic procedure. ... expected to lead advances in identification of better treatment and gene therapy in a new era of precision medicine for genetic
[156] Genetic testing for neurodegenerative diseases: Ethical and health ... — Advances in genetic testing for neurodegenerative conditions have improved the ability to make accurate diagnoses, provide recurrence risk information to family members, and (in some cases) determine eligibility for clinical trials. ... As an increasing number of pathogenic variants have been identified across several neurological diseases, use
[157] Advances in genetic diagnosis of neurological disorders — Nevertheless, detailed genetic and molecular characterizations might in the future translate into personalized and better treatment options for patients with these common disorders 13. Genetic testing today. The neurological diagnostic process starts with the anamnesis followed by a clinical neurological and general examination.
[185] Neurogenetics: Precision Medicine-Based Approaches to Neurological ... — This review paper delves into the role of precision medicine in neurogenetics, focusing on neural stem cells, induced pluripotent stem cells (iPSCs), genetic profiling, and pharmacogenetics within the contexts of Alzheimer's disease and schizophrenia. By evaluating current achievements alongside existing challenges, this paper underscores
[186] (PDF) Neurogenetics: Precision Medicine-Based Approaches to ... — This review paper delves into the role of precision medicine in neurogenetics, focusing on neural stem cells, induced pluripotent stem cells (iPSCs), genetic profiling, and pharmacogenetics within
[190] Clinical implications of neuropharmacogenetics - PubMed — Results: Several pharmacogenetic studies have been performed in neurology, bringing insights into the inter-individual drug response variability and in the pathophysiology of neurological diseases. The principal implications of these studies for the management of patients in clinical practice are discussed.
[191] PDF — Pharmacogenetics will surely become part of standard considerations in the use of pharmaceuticals. Results of the contemporary farmacogenetics research are nding an increasing role in clinical practice, yet the practicing physician often does not have at hand the rel-evant information in the appropriate form. For that reason
[193] Pharmacogenomics in Clinical Practice - PubMed Central (PMC) — The lack of clinical practice guidelines and algorithms is an additional barrier to the translation of pharmacogenetics into clinical practice. 2, 6, 9 Guidelines need to be robust, up to date, and consistent but also flexible so that they can be quickly revised to reflect new research findings. 11 In order to facilitate developments in this
[194] PDF — Barriers to integration of pharmacogenetic tests into clinical care • Fragmentation of health-care systems---esp over a lifetime • Health-care delivery system and incentive structures are focused on sick care and not disease prevention • Lack of evidence of clinical utility or cost effectiveness--coupled with excessively high requirements
[200] Point of view: Challenges in implementation of new ... - PubMed — These challenges include determining patient eligibility, appropriate use of diagnostic tools and genetic testing in patient care pathways, effective detection and monitoring of side effects, and improving the healthcare system's readiness by engaging both primary care and dementia specialists.
[201] Challenges and opportunities in neurodegenerative diseases management — Challenges and opportunities in neurodegenerative diseases management - ScienceDirect Chapter 24 - Challenges and opportunities in neurodegenerative diseases management Resource limitations, including financial constraints, access to specialized care, and insufficient caregiver support, further complicate the management of these disorders. This chapter presents a comprehensive overview of the challenges and opportunities in managing neurodegenerative diseases, highlighting the need for collaborative multidisciplinary care models and comprehensive policies that address these disorders' social, economic, and ethical implications. Copyright © 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Brain Research, Volume 1850, 2025, Article 149392 All rights are reserved, including those for text and data mining, AI training, and similar technologies.
[202] Implementing a tridimensional diagnostic framework for personalized ... — 1 INTRODUCTION Neurodegenerative diseases (NDDs) pose significant challenges to modern medicine due to their complex etiologies, clinical variability, and frequent co-occurrence of multiple pathologies. Traditional classifications have relied on clinical symptoms and post mortem findings, yet these approaches fail to capture the intricate molecular, genetic, and temporal dynamics that
[205] Genetic therapies for neurological disorders | Human Genetics - Springer — In recent years, it has become increasingly apparent that many neurological disorders are underpinned by a genetic aetiology. This has resulted in considerable efforts to develop therapeutic strategies which can treat the disease-causing mutation, either by supplying a functional copy of the mutated gene or editing the genomic sequence. In this review, we will discuss the main genetic
[218] Neurogenetic Testing: Latest Advances in 2024 - DrOmics Labs — In summary, the latest advances in neurogenetic testing are ushering in a new era of personalized medicine in neurology. By leveraging genetic insights, we can move towards more precise, effective, and individualized care for patients with neurological disorders, ultimately improving their quality of life.
[219] NGS-Based Diagnosis of Treatable Neurogenetic Disorders in Adults ... — The genotype-first diagnostic process has become common with the recent advances and increasing availability in clinical settings of genetic technologies, including NGS and DNA microarray, bringing with it greater opportunities for diagnosing patients and multiple family members .
[220] Gene therapies for neurogenetic disorders - ScienceDirect — The breathtaking advances in diagnosing and treating genetic disorders mandate that insights from researchers and geneticists inform clinical practice. This knowledge can transform patient lives, especially as technologies to modify gene expression and replace or edit genes or the epigenome move to the clinic.
[221] Molecular diagnostic approach to rare neurological diseases from a ... — Advancements in sequencing technology have significantly enhanced diagnostic capabilities for rare neurological diseases. This progress in molecular diagnostics can greatly impact clinical management and facilitate the development of personalized treatments for patients with rare neurological diseases. Neurologists with expertise should raise clinical awareness, as phenotyping remains crucial
[224] Genetic overlap between schizophrenia spectrum disorders and Alzheimer ... — Schizophrenia and Alzheimer's disease (AD) are two distinct neurological disorders that affect millions of individuals worldwide, both of which have prominent genetic components, with schizophrenia having an estimated heritability of approximately 80 % (Sullivan et al., 2003), and AD having an estimated heritability ranging from 60 % to 80 % (Gatz et al., 1997).
[225] Genetic overlap between schizophrenia spectrum disorders and Alzheimer ... — The genetic correlations between schizophrenia and AD were weak but positive (r g =0.03-0.10). Polygenic risk scores (PRSs) for schizophrenia and AD indicate some genetic predisposition, although findings are inconsistent among studies; e.g., PRS-schizophrenia or PRS-AD were associated with the risk of developing psychosis in patients with AD.
[226] A screen of 1,049 schizophrenia and 30 Alzheimer's-associated ... - PubMed — Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer's disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay to screen, 1,049 SZ and 30 AD variants in …
[229] Ethical Issues in Neurogenetics - PMC - PubMed Central (PMC) — Different applications of genetic testing for neurogenetic conditions (e.g. predictive and prenatal) and the patient’s age (e.g. minor) can raise ethical issues (Fuentes and Martin-Arribas, 2007; Hedera, 2001; Hoge and Appelbaum, 2012; Roberts and Uhlmann, 2013; Schneider et al., 2011; Uhlmann, 2006). The National Society of Genetic Counselors (2012) issued a position statement encouraging deferring predictive genetic testing of minors for adult-onset conditions: “Deferring predictive genetic testing allows individuals to choose for themselves as adults, taking into account their own circumstances, preferences and beliefs (National Society of Genetic Counselors, 2012).” The American College of Medical Genetics and Genomics (ACMG) jointly with the American Academy of Pediatrics (AAP) issued a policy statement in 2013 which reaffirmed their continued support to defer genetic testing of children for adult-onset conditions until adulthood (Ross et al., 2013; American Academy of Pediatrics, Committee on Bioethics, Committee on Genetics and American College of Medical Genetics and Genomics Social, Ethical and Legal Issues Committee, 2013).
[230] Ethical issues in neurogenetics - PubMed — Predictive genetic testing offers asymptomatic relatives the opportunity to determine their risk status for a neurogenetic condition, and professional guidelines emphasize patients' autonomy and informed, voluntary decision making. The ethical implications of genetic testing and emerging issues, including direct-to-consumer genetic testing, disclosure of secondary findings from genomic sequencing, and use of apolipoprotein E testing in clinical and research settings, are also discussed. Keywords: autonomy; cognitive impairment; decisional capacity; direct-to-consumer (DTC); ethical issues; genetic testing; incidental findings; neurogenetic conditions; predictive testing; secondary findings; testing children. Genetic susceptibility testing for neurodegenerative diseases: ethical and practice issues. Genetic testing for neurodegenerative diseases: Ethical and health communication challenges. Ethical and policy issues in genetic testing and screening of children. Genetic Testing / ethics*
[231] Ethical issues in neurogenetic disorders - PubMed — The field of neurogenetics is moving so rapidly that new discoveries are announced almost weekly. The tools available for the diagnosis of neurogenetic disorders have become powerful and complex, and raise new ethical dilemmas that did not exist just a few years ago. In addition to previous concerns …
[234] What is considered neurogenetics? - genetics4medics.com — Ethical Considerations in Neurogenetics. Placing the study of neurogenetics at the forefront of scientific inquiry raises significant ethical questions. The ability to manipulate or alter genetic information can potentially lead to unforeseen consequences. Concerns regarding consent, particularly in vulnerable populations, underscore the need
[235] Ethical Considerations in Neurogenetic Testing - PubMed — However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions. This review summarizes ethical issues related to genetic testing for neurologic diseases, with a focus on clinical practice. Disclosure and its consequences for the patient are placed within an ethical framework to permit a better understanding of why genetic testing is different from most other diagnostic testing ordered by physicians.
[236] Ethical Issues in Neurogenetics - PMC - PubMed Central (PMC) — Different applications of genetic testing for neurogenetic conditions (e.g. predictive and prenatal) and the patient’s age (e.g. minor) can raise ethical issues (Fuentes and Martin-Arribas, 2007; Hedera, 2001; Hoge and Appelbaum, 2012; Roberts and Uhlmann, 2013; Schneider et al., 2011; Uhlmann, 2006). The National Society of Genetic Counselors (2012) issued a position statement encouraging deferring predictive genetic testing of minors for adult-onset conditions: “Deferring predictive genetic testing allows individuals to choose for themselves as adults, taking into account their own circumstances, preferences and beliefs (National Society of Genetic Counselors, 2012).” The American College of Medical Genetics and Genomics (ACMG) jointly with the American Academy of Pediatrics (AAP) issued a policy statement in 2013 which reaffirmed their continued support to defer genetic testing of children for adult-onset conditions until adulthood (Ross et al., 2013; American Academy of Pediatrics, Committee on Bioethics, Committee on Genetics and American College of Medical Genetics and Genomics Social, Ethical and Legal Issues Committee, 2013).
[238] Ethical Issues in Genetic Testing - ACOG — Many incidental findings will come to light, and yet, although those tested may be tempted to believe otherwise, genetic findings do not equate directly with either disease or health: “one hundred percent accurate identification of such incidental pathologies will lead to iatrogenic pathology… the belief that genetics completely determines phenotypic outcome must be informed by an understanding that most genetic measurements only shift the probability of an outcome, which often depends on other environmental triggers and chance” 4.
[239] Analysis of state laws on informed consent for clinical genetic testing ... — Informed consent rules are derived from a complex intersection of state and federal case law, statutes, and regulations (e.g., state laws on general clinical informed consent and relevant federal anti-discrimination legislation such as the Americans with Disabilities Act (ADA) and the Genetic Information Nondiscrimination Act (GINA)).
[241] Informed Consent - National Human Genome Research Institute — Informed consent is an integral part of the genomics research endeavor. Since sequencing a person’s genome can have implications for identity and privacy, the informed consent process is an important touchstone to maintain research participant autonomy. In designing an effective informed consent process for genomics research, researchers should consider the information participants may need to understand risks and potential benefits of participating in the study. The NHGRI Informed Consent Resource, originally created in 2010 and continuously maintained, provides sample language for informed consent forms and additional information about the required elements for informed consent and the special considerations for genomics research. GDS Policy Sample Informed Consent LanguageSample informed consent language, aligned with each of the informational elements of consent for genomic data sharing (GDS) outlined by NIH as important to convey, in language understandable to prospective participants.
[244] NHGRI researchers work with patients, families and the scientific ... — NHGRI researchers work with patients, families and the scientific community to improve the informed consent process . As genome-editing trials become more common, informed consent is changing. As public interest and expanded research in human genome editing grows, many questions remain about ethical, legal and social implications of the technology.
[246] The Ethics of Crispr: Debating the Moral Implications of Gene Editing — The ethical considerations surrounding CRISPR involve pondering the potential consequences of gene editing within the realms of bioethics and morality. With the potential to fundamentally alter the genetic makeup of future generations, gene editing necessitates rigorous ethical considerations. This ability to manipulate the genetic makeup of individuals before they are even born raises profound ethical concerns surrounding the alteration of human nature, the potential for unintended consequences, and the boundaries of our moral responsibility towards future generations. The morality and ethical considerations surrounding the use of Crispr raise important questions about our role in altering the genetic makeup of living organisms and the potential consequences for ecosystems.
[260] The law of genetic privacy: applications, implications, and limitations ... — Key recommendations found in the Best Practices document include (1) ‘Detailed transparency about how Genetic Data is collected, used, shared, and retained including a high-level summary of key privacy protections posted publicly and made easily accessible to consumers’; (2) ‘Separate express consent for transfer of Genetic Data to third parties and for incompatible secondary uses’; (3) ‘Educational resources about the basics, risks, benefits, and limitations of genetic and personal genomic testing’; (4) ‘Access, correction, and deletion rights’; (5) ‘Valid legal process for the disclosure of Genetic Data to law enforcement and transparency reporting on at least an annual basis’; (6) ‘Ban on sharing Genetic Data with third parties (such as employers, insurance companies, educational institutions, and government agencies) without consent or as required by law’; (7) ‘Restrictions on marketing based on Genetic Data’; and (8) ‘Strong data security protections and privacy by design, among others’.
[261] Legislation on Genetic Privacy: Understanding the New Legal Landscape ... — The intersection of biotechnology and privacy law has garnered significant attention, particularly regarding legislation on genetic privacy. As advancements in genetic testing proliferate, the need for robust legal frameworks to protect individuals' genetic information has become increasingly urgent.
[265] Databases for neurogenetics: Introduction, overview, and challenges ... — Another challenge for the development of LSDBs in neurogenetics comes from the nature of some of the mutation types frequently encountered in neurodegenerative diseases. Expansions of repetitive elements in the genome, also called dynamic mutations, underlie neurological disorders such as Huntington disease, fragile-X mental retardation, and
[266] Neurogenetic Disease: Genes, Mechanisms, and Future Promise — The great hope for the future is that this information can be translated into similarly revolutionary therapies, though the pace of therapeutic development has been disappointing. Nevertheless, new delivery vehicles and methods for precise gene editing have fueled progress and justifiable excitement in this area, as reviewed by Maguire et al
[267] The Neurogenetics Collection: emerging themes and future considerations ... — In a recent issue of Brain, two groups implicated rare variants in the HTRA1 gene in the occurrence of white matter hyperintensities in the general population.16,17 Together, these studies show the value of examining rare variants as a cause of common diseases.18 They also illustrate that heterozygous variants located within autosomal recessive genes are not always benign, a disease pattern predicted by Vogel nearly 40 years ago.19 Aside from the clinical importance of their findings, both papers illustrate a growing trend in genetics, namely the use of large public datasets to support their work.
[268] Ethical considerations of gene editing and genetic selection — At the end of the summit, the organizing committee released a statement advising ongoing global engagement and discussion, and outlined their conclusions regarding gene editing: 97 “(i)ntensive basic and preclinical research is clearly needed and should proceed, subject to appropriate legal and ethical rules and oversight…”; “(m)any promising and valuable clinical applications of gene editing are directed at altering genetic sequences only in somatic cells… [and] they can be… evaluated within existing and evolving regulatory frameworks for gene therapy…”; and “(g)ene editing might also be used, in principle, to make genetic alterations in gametes or embryos…” The statement goes on to address the ethical, legal, and scientific questions surrounding germline editing that have yet to be answered, and warns: Tang L, Zeng Y, Du H, Gong M, Peng J, Zhang B, et al CRISPR/Cas9‐mediated gene editing in human zygotes using Cas9 protein.
[269] Balancing potential benefits and ethical considerations of gene editing — Although the potential benefits of gene editing are enormous,1 considering that it also presents serious ethical, scientific, and social challenges that must be addressed is important.2 A recent Editorial3 highlights heritable genome editing risks and urges regulatory clarity to prevent unintended generational changes.4 Reproductive embryo DNA alteration is banned in many countries, but
[270] What are the Ethical Concerns of Genome Editing? — Most of the ethical discussions related to genome editing center around human germline because editing changes made in the germline would be passed down to future generations. Overview The debate about genome editing is not a new one but has regained attention following the discovery that CRISPR has the potential to make such editing more accurate and even "easy" in comparison to older technologies. As of 2014, there were about 40 countries that discouraged or banned research on germline editing, including 15 nations in Western Europe, because of ethical and safety concerns.3 There is also an international effort led by the US, UK, and China to harmonize regulation of the application of genome editing technologies. Researchers and ethicists who have written and spoken about genome editing, such as those present at the International Summit on Human Gene Editing, generally agree that until germline genome editing is deemed safe through research, it should not be used for clinical reproductive purposes; the risk cannot be justified by the potential benefit. Researchers and bioethicists also worry about the possibility of obtaining truly informed consent from prospective parents as long as the risks of germline therapy are unknown.10 Justice and Equity As with many new technologies, there is concern that genome editing will only be accessible to the wealthy and will increase existing disparities in access to health care and other interventions.
[271] Gene Editing: Developments, Ethical Considerations, and Future ... — With the advent and patenting of CRISPR technology, the National Academy of Science and the National Academy of Medicine launched the Human Genome Editing Initiative in 2015 to create an informed decision-making process on germline editing experiments.4 The initiative has organized three international summits that convene experts in the field to discuss advances and ethical frameworks for such technologies. Because of Jiankui’s 2019 experiment, The National Institutes of Health, expert bioethicists, and many pioneers of CRISPR technology called for a temporary moratorium on all human-based embryo gene editing.11 The organizing committee of the Third International Summit on Human Genome Editing reaffirmed this decision in 2023, stating that human germline editing is not acceptable since safety, ethical, and government standards have not been met for implementation of germline therapies.12
[274] Approach to diagnosis and management of genetic neurodevelopmental ... — All individuals with GDD/ID, ASD, and CP should be offered genetic evaluation. There are a multitude of potential benefits of a genetic diagnosis, including reproductive counseling, changes in medical management, initiation of systemic surveillance, facilitation of family testing, access to clinical trials and/or advocacy groups, and termination of the diagnostic odyssey , , , .
[275] Genetic testing in adults with neurologic disorders: indications ... — The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. ... Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts J Neurol. 2024 Feb
[282] Human Mutation - Wiley Online Library — Expansions of repetitive elements in the genome, also called dynamic mutations, underlie neurological disorders such as Huntington disease, fragile-X mental retardation, and several SCA, among others. These oligonucleotide repeats amenable to pathologic expansions vary in structure, size and location of the repetitive element within the gene.
[283] Gene therapies for neurogenetic disorders - ScienceDirect — Gene therapies for neurogenetic disorders - ScienceDirect Gene therapies for neurogenetic disorders Open access The need to cross the blood–brain barrier, the post-mitotic nature of neurons, and inefficient delivery platforms limit gene therapies for neurological diseases. Innovation in regulatory and commercial pathways is needed to advance the translation and reduce the time and cost of developing gene therapies for neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood–brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders. For all open access content, the relevant licensing terms apply.
[285] Gene therapies for neurogenetic disorders - PubMed — Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies
[286] Enhancing variant of uncertain significance (VUS) interpretation in ... — Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics
[287] Benefits and Challenges of Rare Genetic Variation in Alzheimer's ... — The gold standard for rare variant discovery remains WGS, assaying every base in the genome. WGS allows the analysis of the full range of genomic modifications including pathogenic variants, structural variants and variants in non-coding regulatory regions .Additionally, WGS is the superior method for covering difficult genomic regions including those with high GC content due to
[288] Gene family information facilitates variant interpretation and ... — Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for
[289] UniVar: A variant interpretation platform enhancing rare disease ... — Interpreting the pathogenicity of genetic variants associated with rare diseases is a laborious and time-consuming endeavour. To streamline the diagnostic process and lighten the burden of variant interpretation, it is crucial to automate variant annotation and prioritization.
[290] Molecular diagnostic approach to rare neurological diseases from a ... — This progress has deepened our understanding of pathomechanisms and ultimately led to the development of specific therapeutic options for rare diseases (RD). This is particularly true for rare neurogenetic diseases. Approximately 80% of rare diseases have genetic origins, with nearly half of these conditions affecting the nervous system.