American Society Of Human Genetics Research Articles

Editorial introductions.

Current Opinion in Neurology was launched in 1988. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of neurology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Lawrence J. HirschLawrence J. HirschLawrence J. Hirsch, MD is Professor of Neurology, Chief of the Division of Epilepsy and EEG, and Co-Director of the Comprehensive Epilepsy Center, all at Yale University, USA. He has held leadership positions in the American Clinical Neurophysiology Society (ACNS), American Epilepsy Society, American Academy of Neurology, and the Epilepsy Foundation, and is lead author of the 2012 and 2021 ACNS guidelines on critical care EEG terminology. He is founder and former chair of the Critical Care EEG Monitoring Research Consortium, which now includes more than 50 centers, and co-chair of the medical advisory board of the NORSE Institute. He has been an active researcher throughout his career, having published more than 200 peer-reviewed manuscripts and more than 100 reviews, editorials or book chapters on topics including status epilepticus, all aspects of EEG including intracranial recordings and brain monitoring in the critically ill, brain stimulation, epilepsy surgery, seizure clusters, rescue medications, sudden death in epilepsy (SUDEP), and anti-seizure medication use. He has won multiple teaching awards and is co-author of the first-ever atlas on EEG in critical care, now in its 2nd edition. He continues to see patients in the inpatient and outpatient setting, direct fellowship programs, teach, mentor, and manage a large epilepsy division at a level IV Comprehensive Epilepsy Center. Michael F. WatersMichael F. WatersMichael F. Waters, MD, PhD, is a neurologist, director of both the Neurovascular Division and the Petznick Stroke Center, and a professor in the Department of Neurology at Barrow Neurological Institute, USA. He is board certified in neurology by the American Board of Psychiatry and Neurology with subspecialty board certification in vascular neurology. Dr Waters’ expertise is stroke and neurovascular disease, including signs, symptoms, diagnostics, and treatments. He is a fellow of both the American Academy of Neurology and American Heart Association and a member of the American Neurological Association, American Society of Human Genetics, and the Society of Vascular and Interventional Neurology. Dr Waters received his Masters in genetics from Penn State University in State College, Pennsylvania, USA, and his doctorate in biochemistry and molecular biology from The University of Florida College of Medicine in Gainesville, USA, where he also completed his MD. He completed his residency training at the University of California – Los Angeles Department of Neurology and completed his fellowship in clinical and molecular neurogenetics at Cedars Sinai Medical Center in Los Angeles, USA. Dr Waters’ research studies include genetic mechanisms of stroke, neuroprotection in stroke, stroke treatment, multiple clinical trials investigating stroke treatments, and neurogenetic mechanisms of neuroplasticity.

Variation among DNA banking consent forms: points for clinicians to bank on

Deoxyribonucleic acid (DNA) banking is an important laboratory service that preserves the option of future genetic testing. DNA bank consent forms are a critical tool to facilitate thorough and valid informed consent. The objectives of this study were to assess the level of consistency of current clinical DNA banking consent forms with the American Society of Human Genetics (ASHG) and the American College of Medical Genetics and Genomics (ACMG) guidance and to explore variation among the forms. The content analysis matrix included key points identified from the ASHG and ACMG documents (including benefits/risks, sample storage, access, disposition, and communication) and additional points beyond the ASHG and ACMG documents identified from the consent forms themselves during the analysis process. Forms were assessed for language addressing each point. Five consent forms were identified and analyzed for twelve key points and eight additional points. The average consistency for key points was 10.8/12 (range 8/12 to 12/12). The range for additional points was 1/8 to 5/8. There was variation across forms in the details provided related to key and additional points. Gaps in clinical DNA banking consent forms are barriers to achieving informed consent. Clinicians can consider the consent key and additional points discussed here to supplement and enrich their clinical DNA banking informed consent discussions, promote stewardship, and maximize downstream utility of banked DNA. The identification of multiple additional points beyond the ASHG and ACMG documents' key points indicates a need for this guidance to be updated.

Letters to the Editor

To the Readers of ABT:In July 2022, the scientific community will celebrate the 200th birthday of Gregor Mendel, the founder of genetics. This journal will kick off the year in January with a special issue devoted to the illustrious abbot and the field he created, but high school biology students can reflect now on Mendel’s legacy by participating in the annual DNA Day essay contest, sponsored by the American Society of Human Genetics. You can find the question at https://www.ashg.org/dna-day/. The deadline for essays is in early March 2022, with winners announced the following month.John J. Mulvihill, University of Oklahoma School of MedicineJoseph D. McInerney, NABT president 1991I would like to bring to your attention a problem in the article “Connecting Ideas across Courses: Relating Energy, Bonds & How ATP Hydrolysis Powers a Molecular Motor” (May 2021). The article contains a sentence in which students are asked to recall information about the role of energy in bond breaking and forming -- especially that energy is required to break covalent bonds and that energy is released when bonds are formed – as well as to describe what they know about how ATP is used to support cellular functions. This sentence and the chart on the next page are in direct opposition to what really happens when bonds are formed and broken. What really occurs is that energy is stored in the bonds that form in molecules such as Adenosine triphosphate (ATP) acting like money in the bank. This energy can be used later and is released when bonds are broken, typically in mitochondria.

Privacy practices using genetic data from cell-free DNA aneuploidy screening

PurposeCell-free fetal DNA (cfDNA) analyzes maternal and fetoplacental DNA, generating highly personal genetic information for both mother and fetus. This study aimed to determine how laboratories retain, use, and share genetic information from cfDNA. Other outcomes included laboratories’ adherence to American Society of Human Genetics (ASHG) privacy principles, and the readability of privacy policies. MethodsLaboratories offering cfDNA aneuploidy screening were identified from online searches, curated databases, and a genomics news website. Of 124 laboratories identified, 13 were commercial laboratories offering cfDNA aneuploidy screening in the United States, and were included. Genetic privacy policies from eligible laboratories were identified by reviewing requisition and consent forms, which were obtained online or by direct contact. ResultsMost laboratories use prenatal genetic information for research (n = 10, 77%), and more than half (n = 7, 54%) shared genetic information with others. Overall, laboratories inadequately disclosed privacy risks. In a readability analysis, 9 of 11 (82%) laboratories’ genetic privacy policies were written at or above a 12th grade reading level. ConclusionMost laboratories allowed for prolonged use and sharing of cfDNA data, demonstrated incomplete adherence to ASHG privacy recommendations, and provided consents written in college-level language. Laboratories should revise their consent forms, and providers should help patients understand these forms.

Genetic counseling: development of requirements, contents, and quality management in Germany.

To carry out quality management of genetic counseling, it is important to know what genetic counseling exactly means and who the players are. The term "genetic counseling" was first defined by Reed in 1947. It describes a communication process dealing with genetic facts and psychosocial aspects and is an education process, too. It has always been understood in the context of individual and family problems, and is unrelated to eugenics. In 1975 the Ad Hoc Committee of the American Society of Human Genetics published a more detailed description. With the development of new diagnostic techniques and methods in human genetics, the requirements of genetic counseling and its contents changed. Today a genetic counselor has to apply diagnostic, predictive, susceptibility, pharmacogenetic, carrier, prenatal, and preimplantation testing, as well as genetic screening. The German Human Genetic Examination Act (Genetic Diagnosis Act - GenDG) and national and international associations recommend to embed genetic testing into genetic counseling. Based on experiences of the author, some examples of pitfalls in genetic counseling are illustrated, as there are so many individual situations and requests that it seems impossible to carry out quality management. Nevertheless, the Commission for Quality in Genetic Counseling and Clinical Genetics of the Professional Association of German Human Geneticists started a pilot ring trial in 2018 with a given counseling situation. The task was to write the human genetics comment with the help of a checklist containing all issues necessary. The evaluation was conducted with the help of a catalogue of criteria which had been established beforehand and a score adjusted to the individual situation. The first genuine pilot trial was launched in 2020. It represents a possibility for quality management in genetic counseling.

The man behind the honors Dr. P. M. MacLeod MD FRCPC FCCMG DABG.

The man behind the honors Dr. P. M. MacLeod MD FRCPC FCCMG DABG.

Genome Diagnostics: Novel Strategies for Measuring Value.

Genetic testing technology is rapidly evolving with the growth of personalized medicine. While test evaluation typically relies on laboratory measures of performance, tests can be costly and analytically and ethically complex. A more fulsome consideration of value is warranted to inform adoption and appropriate use. Herein we describe a methodology for developing novel clinician- and patient-reported measures of clinical and personal utility, aiming to capture the informational value of genome diagnostic tests. Adhering to core measurement science principles and standards, our 4-step process includes (1) tool development through scoping reviews and stakeholder interviews and surveys; (2) tool validation through prospective cohort studies to establish construct validity, inter- and intra-rater reliability; (3) tool application using comparative effectiveness assessment to gauge the comparative value of different types of genetic tests; and (4) tool dissemination, leveraging existing partnerships with international stakeholders to spur additional validation studies, comparative effectiveness research, cost-effectiveness analysis, and evidence-informed policy. A scoping review of the clinical utility literature informed the development of a preliminary 25-item index. Qualitative interviews with 35 clinicians further informed the definition of our utility construct, item content, and item importance. Stakeholder surveys with 113 clinicians enabled further feedback on item content, importance, sensibility, response, and scoring options. An 18-item tool, the "Clinician-reported Genetic testing Utility InDEx" (C-GUIDE), is now undergoing validation, while development work on the patient-reported measure of utility is underway. A methodologically innovative approach to the development of stakeholder-informed and clinimetrically sound measures of value for personalized medicine tests will assist technology users and decision makers globally. DISCLOSURES: This work was supported by the Canadian Institutes of Health Research Operating Grant (#PJT-152880) and the PhRMA Foundation Challenge Award. Publication of the study methodology or findings generated therein was not contingent on the sponsor's approval or censorship of the manuscript. The authors have nothing to disclose. Results from this study were presented as a poster at the 40th Annual North American Meeting of the Society for Medical Decision Making; October 14, 2018; Montreal, QC; the Annual Meeting of the American Society of Human Genetics; October 18, 2018; San Diego, CA; and as an oral presentation at the Annual Meeting of the Canadian Association for Health Services and Policy Research; May 31, 2018; Montreal, QC.

Genetics professionals' attitudes toward prenatal exome sequencing.

Prenatal exome sequencing (ES) currently has limited use in the clinical setting, but research suggests that it has added diagnostic utility over karyotyping and array techniques for prenatal diagnosis of fetuses presenting with ultrasound abnormalities. The purpose of this study was to assess the attitudes of genetics professionals toward the clinical implementation of prenatal ES in order to guide development of professional guidelines. A survey was developed using themes identified in previous qualitative studies and was distributed to members of the American College of Medical Genetics and Genomics (ACMG), the American Society of Human Genetics (ASHG), and the National Society of Genetic Counselors (NSGC). A total of 498 participants completed some portion of the survey. There was consensus among participants that there would be clinical utility of prenatal ES when used for diagnosis, pregnancy management, and termination decisions. The majority also agreed that prenatal ES was distinct from its current use in the pediatric and adult settings. There were many areas of contention regarding which types of results should be returned to families and whether or not the current ACMG guidelines for return of incidental findings should also apply to the prenatal setting. Overall, professional guidance is needed to address the continuing concerns surrounding prenatal ES as its utilization in this setting is expected to grow.

2018 ASHG Awards and Addresses

Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of theSocietyand a number of award winners. A summary of each of these is provided below. On the following pages, we haveprintedthe Presidential Address as well as the addresses for the William Allan Award, the Curt Stern Award, and the McKusickLeadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.

2018 Curt Stern Award Address

This article is based on the address given by the author at the meeting of the American Society of Human Genetics (ASHG) on October 18, 2018, in San Diego, California. The audio of the original address can be found at the ASHG website.

Just choice: a Danielsian analysis of the aims and scope of prenatal screening for fetal abnormalities

Developments in Non-Invasive Prenatal Testing (NIPT) and cell-free fetal DNA analysis raise the possibility that antenatal services may soon be able to support couples in non-invasively testing for, and diagnosing, an unprecedented range of genetic disorders and traits coded within their unborn child’s genome. Inevitably, this has prompted debate within the bioethics literature about what screening options should be offered to couples for the purpose of reproductive choice. In relation to this problem, the European Society of Human Genetics (ESHG) and American Society of Human Genetics (ASHG) tentatively recommend that any expansion of this type of screening, as facilitated by NIPT, should be limited to serious congenital and childhood disorders. In support of this recommendation, the ESHG and ASHG cite considerations of distribution justice. Notably, however, an account of justice in the organization and provision of this type of screening which might substantiate this recommendation has yet to be developed. This paper attempts to redress this oversight through an investigation of Norman Daniels’ theory of Just health: meeting health needs fairly. In line with this aim, the paper examines what special moral importance (for Just health) screening for the purpose of reproductive choice might have where concerning serious congenital and childhood disorders in particular. The paper concludes that screening for reproductive choice where concerning serious congenital and childhood disorders may be important for providing women with fair opportunity to protect their health (by either having or not having an affected child).

Prohibiting Genetic Discrimination to Promote Science, Health, and Fairness

Protections against genetic discrimination advance genetics research and the clinical use of genetics, as well as ensure the ethical use of genetic data. Ten years after the passage of the Genetic Information Nondiscrimination Act (GINA), the American Society of Human Genetics remains a staunch advocate for GINA's strong implementation and for other laws that enhance protections for the public.

2017 ASHG Awards and Addresses

Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.

Dennis Luke Murphy, M.D. (1936-2017).

The name Dennis Murphy is known to everyone in monoamine research. His life's research was devoted to investigations of alterations in neurotransmitter systems in psychiatric disorders. He was a rare scientist who focused on all levels of research—basic, translational, and clinical—and spanning neurochemical, genetic, molecular, clinical pharmacology, and behavioral approaches. His early work included investigations on the mechanisms of action of levodopa,1-3 lithium,4, 5 and extensive research on monoamine oxidase (References 6-9 plus over 130 papers). He authored a seminal paper on the linked-polymorphic region in the serotonin transporter (SERT) gene promoter10—a hallmark in the “birth” of the field of psychiatric genetics. He developed the SERT knockout mouse,11-13 and used this and other genetic mouse models to investigate mood and anxiety disorders.14-16 His genetic work included functionality-informed candidate gene studies of the SERT gene SLC6A417, 18 and the neuronal glutamate transporter gene SLC1A1,19 and the genetics of obsessive–compulsive disorder.20 The list goes on. Over his career, he authored over 800 papers, more than 100 book chapters, and 4 books. Dr. Murphy's successes also include training and mentoring more than 100 students and fellows. The list of success stories of those he mentored is extensive, and includes chairs and professors of psychiatry and basic science departments around the world; impactful leaders serving as principal investigators and administrators in industry and government; and even a former NIMH Director. As a mentor, he strongly encouraged and supported a multidisciplinary environment of creativity and exploration, and enjoyed sharing opportunities to think outside the box. His command of the literature, and his insights into many areas of basic, translational, and clinical neuroscience, were second to none. As much enthusiasm as Dennis had for science, he had equal excitement for life outside the lab. He was an avid traveler, hiker, skier, and a tennis enthusiast; these activities were well known to his trainees and colleagues alike, who often joined Dennis on the slopes, the courts, or the Billy Goat Trail. For Dennis, photography could easily have been an equally successful second career. His personality and genuine interest in numerous non-scientific areas made every interaction, be it as a scientific mentor or friend, delightful and, more often than not, memorable. Dr. Murphy received his Bachelor of Science degree from Marquette University in 1958, his Medical and Master of Science degrees from the Medical College of Wisconsin in 1963, and he completed his residency in psychiatry at the Johns Hopkins University in 1966. He joined NIMH as a Clinical Fellow in 1966 and became Chief of the Clinical Neuropharmacology Branch in 1977, which was incorporated within the Laboratory of Clinical Science in 1983. Beyond his research, Dr. Murphy contributed significantly to the scientific community. He served on Editorial Boards for numerous journals, such as Biological Psychiatry, Neuropsychopharmacology, and Progress in Neuropsychopharmacology. In addition to extensive service at NIMH and NIH, he served on numerous Councils, Advisory Boards, and Consortia around the world. Examples include: the Riken Brain Science Institute (Tokyo); the Swedish Medical Research Council; the Ontario Mental Health Foundation; the National Alliance for Research in Schizophrenia and Depression (NARSAD); The Burroughs Wellcome Fund; the Howard Hughes Medical Institute; and, the German-Israeli Foundation for Scientific Research and Development. He was also a member of several professional societies, including the American College of Neuropsychopharmacology (ACNP), the Collegium Internationale Neuropsychopharmacologium (CINP), and the American Society of Human Genetics. Dr. Murphy received numerous awards and distinctions throughout his career, including, among others: 2 Presidential Meritorious Executive Rank Awards; the U.S. Public Health Service's Superior Service Award; the Department of Health and Human Services' Distinguished Service Award; the Alcohol, Drug Abuse and Mental Health Administration's Meritorious Service Award; the American Psychiatric Association's Hofheimer Prize for Research; and, the Society for Biological Psychiatry's A.E. Bennett Award for Clinical Research. The legacy of Dr. Dennis Murphy extends far beyond his substantial body of research and his publications. Perhaps most importantly, his legacy is the many he trained and mentored and to whom he generously afforded opportunities, including the 3 authors of this brief chronicle of his life. The authors declare no potential conflict of interests.

Forging the path for PRecISion Medicine in Autism: The PRISMA Neurogenetic Psychiatry Consultation Service

Psychiatry is at a pivotal stage; advances in neuroscience and genetics are allowing us to understand more clearly how specific changes in neurodevelopment and genetic architecture are contributing to increased risk for several mental health disorders. Nowhere has progress been clearer than in autism spectrum disorders (ASDs), one of the psychiatric conditions with the highest genetic burden, as evidenced by their high heritability. Rare variants, which by definition occur in less than 1% of the population, have a large impact on the etiology of autism, as together they can explain up to 30% of cases of autism. These include highly penetrant copy number variants (CNVs), defined as losses or gains of genetic material, and single nucleotide variants (SNVs), characterized by changes in single base pairs. Because of the increased risk these rare variants confer, many professional societies, including the American Society of Human Genetics and the American College of Medical Genetics and Genomics jointly, the American Academy of Child and Adolescent Psychiatry, and others have recommended genetic testing as the standard of care or a key step in the workup of cases of ASDs. However, the adoption of these recommendations in psychiatry clinics has been quite low. In fact, only close to 5% of patients receive these tests in our population (submitted), which means that the overwhelming majority of people with ASDs are not benefiting from genetically informed health care.

Adoptees' Pursuit of Genomic Testing to Fill Gaps in Family Health History and Reduce Healthcare Disparity.

In the symposium of stories by adoptees who have faced health issues without family health history information, genomic testing is considered as a potentially life-saving means for adoptees to obtain family medical information. The authors share feelings of loss, frustration in healthcare settings, fear of unknown genetic susceptibility to disease, desire for knowledge and self-empowerment in medical decision making, and uncertainty about the utility of genomic testing. Adoptees may pursue ancestry testing, genetic genealogy to find biological relatives, and medical genomic testing. They may choose direct-to-consumer testing because of its affordability and accessibility. Adopted persons are gaining support from healthcare professionals in their pursuit of genomic testing. The National Society of Genetic Counselors' position statement regarding genetic testing and adoption "supports consideration of genetic testing, including genome-wide testing, for adopted adults." However, predictive genomic testing of children in the adoption process is not recommended by the NSGC unless testing may affect childhood medical management. The American Society of Human Genetics and the American College of Medical Genetics and Genomics similarly recommend that genetic testing of children in the adoption process be limited to diagnostic testing for conditions for which there is timely preventative or therapeutic intervention. Going forward, there is responsibility and opportunity for national genetics and genomics societies and healthcare systems to hone their practice guidelines for genomic testing for adoptees. A successful approach will include evidence-based guidelines for genomic testing, inclusion of genetic counseling before and after testing, and return of genomic test results to adoptees' medical homes.

Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study.

As of May 2017, there were 4242 Certified Genetic Counselors (CGC) (American Board of Genetic Counseling, Inc. 2017) and 41 graduate-level genetic counseling training programs (Accreditation Council for Genetic Counseling 2017) in North America, and the demand for CGCs continues to increase. In the Fall of 2015 the Genetic Counselor Workforce Working Group, comprised of representatives from the American Board of Genetic Counseling (ABGC), the Accreditation Council for Genetic Counseling (ACGC), the Association of Genetic Counseling Program Directors (AGCPD), the American Society of Human Genetics (ASHG), and the National Society of Genetic Counselors (NSGC) commissioned a formal workforce study to project supply of and demand for CGCs through 2026. The data indicate a shortage of genetic counselors engaged in direct patient care. Assuming two scenarios for demand, supply is expected to reach equilibrium between 2024 and 2030. However, given the rate of growth in genetic counseling training programs in the six months since the study was completed, it is reasonable to expect that the number of new programs may be higher than anticipated by 2026. If true, and assuming that growth in programs is matched by equivalent growth in clinical training slots, the supply of CGCs in direct patient care would meet demand earlier than these models predict.

Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases.

Recently, many new approaches, study designs, and statistical and analytical methods have emerged for studying gene-environment interactions (G×Es) in large-scale studies of human populations. There are opportunities in this field, particularly with respect to the incorporation of -omics and next-generation sequencing data and continual improvement in measures of environmental exposures implicated in complex disease outcomes. In a workshop called "Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases," held October 17-18, 2014, by the National Institute of Environmental Health Sciences and the National Cancer Institute in conjunction with the annual American Society of Human Genetics meeting, participants explored new approaches and tools that have been developed in recent years for G×E discovery. This paper highlights current and critical issues and themes in G×E research that need additional consideration, including the improved data analytical methods, environmental exposure assessment, and incorporation of functional data and annotations.

2016 ASHG Awards and Addresses

Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is given below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at http://www.ashg.org.

2016 Presidential Address: Let’s Make Human Genetics Great (Again): The Importance of Beauty in Science

Good afternoon. As president of the American Society of Human Genetics (ASHG), it is my pleasure and privilege to welcome you to the 66th annual meeting of our society. It is a particular joy to join you in this beautiful venue in the spectacular city of Vancouver. This eighth visit of ASHG to the great country of Canada marks a particularly important time to acknowledge and applaud the essential contributions of our international colleagues to the vibrancy and relevance of our society. In broader terms, the ability of human genetics as a discipline to deliver on the promise of improving health and wellbeing worldwide in an equitable, just, and sustainable manner will require an unwavering commitment to collaboration, respect, and cultural sensitivity within our community.