GenePod is the podcast from the journal Genetics in Medicine. Join us as host Cynthia Graber delves into the latest research in medical genetics and genomics, featuring content from this leading journal.
One of the challenges in the attempt to standardize variant research, and understand whether a new variant is benign or pathogenic, arises from the fact that the human genome has largely been annotated by two major groups, and they have two different datasets of transcripts: The NCBI, which is based largely in the US, produced the RefSeq database of transcripts, and the EMBL-EBI in Europe produced the Ensembl/GENCODE set of transcripts. In April 2022, a team of researchers introduced the MANE project, or The Matched Annotation from the NCBI and EMBL-EBI , as an attempt to harmonize gene and transcript annotation. While online genome browsers quickly made the change to MANE, not everyone has yet made the switch, as addressed in a recent commentary in Genetics in Medicine. One of the commentary’s authors, Caroline Wright, PhD, professor of genomic medicine at the University of Exeter, joined GenePod to discuss the importance of MANE and its path forward.
Over the past decade, there’s been a running debate about whether to return secondary findings identified during genomic testing of children. The ACMG published a statement in 2013, and again in 2021, recommending disclosing secondary findings to all individuals, including the families of pediatric patients, as the body of evidence in support of such disclosure has accumulated. In a recent study in Genetics in Medicine, “Genomic tools for health: Secondary findings as findings to be shared,” researchers evaluated parents’ potential responses to receiving secondary findings about their child. Skye Miner, PhD, assistant professor of bioethics and medical humanities at University of Arkansas for Medical Sciences, joined GenePod to discuss the results of the survey and their implications for disclosing secondary findings identified in children.
Telemedicine use increased during the COVID pandemic, as did access to telegenetics, but many of the policies that expanded the use of such services during the pandemic are set to expire. To address this urgent problem, the Advocacy and Government Affairs Committee of the American College of Medical Genetics and Genomics recently released a Points to Consider statement, “Considerations for Policymakers to Improve Healthcare through Telegenetics.” Heather Williams, PhD, director of clinical science oncology at Tempus Labs, and David Flannery, MD, director of telegenetics and digital genetics at Cleveland Clinic, joined GenePod to explore what changes can be made to ensure access to telegenetics in the future.
Cystic fibrosis (CF) is thought to be far more common in individuals who self-identify as White than in other groups, and in part that’s because 90 percent of CF registry participants in the US, Canada, and the UK self-identify as White. But a team of researchers took a closer look at Asian CF patients in UK and Canadian registries, plus the registry at Stanford University. They disaggregated the data on South Asian from all other Asian populations, and they were able to both estimate population prevalence, as well as identify pathogenic variants linked to CF in Asian populations. On this month’s GenePod, two of the study’s authors, Zachary M. Sellers, MD, PhD, assistant professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Stanford University, and Sriram Vaidyanathan, PhD, assistant professor and principal investigator at Ohio State University and Nationwide Children's Hospital, discuss the results of their research.
The UK Biobank is a rich source of genetic information and in a previous study, Anna Murray, PhD professor of human genetics at the University of Exeter, mined the biobank to discover new phenotypes for the chromosomal disorder Turner Syndrome in women. In this new study, she and colleagues, including Ken Ong, MD, PhD, professor of pediatric epidemiology and a pediatric endocrinologist at the University of Cambridge, turned their attention to men. On this month’s GenePod, they discuss what they found about the male sex abnormalities Klinefelter Syndrome and XYY, including new data about the risks of adverse health outcomes.
Diagnostic yield, optimal timing, and methodology of next generation sequencing data reanalysis.
Next generation sequencing has becoming increasingly powerful in diagnosing Mendelian disorders, yet typically more than 50 percent of cases remain unsolved after an initial clinical exome or clinical genome sequencing.
As more and more genes are implicated in disease, one of the challenges in implementing genomics in medical practice has been the lack of a single, standardized, and shared genomics database, for both labs and clinicians to access.
When a clinician receives the results of genomic testing, there are several tools that can help the clinician interpret those results: guidelines from ACMG/AMP, the Quest Diagnostic Laboratory scoring system, and the ClinGen gene-disease association framework to name a few.
Multiple studies have demonstrated the clinical benefit of genomic testing for critically ill newborns with rare diseases, but the results could theoretically be returned faster today than they have been in recent years.
Genome sequencing holds great potential to diagnose newborns with phenotypes suggestive of a genetic disorder. However, this technology has not been widely adopted for this population, and particularly not in newborns from underserved and low-income communities.
Matchmaking is an increasingly important strategy to help link rare diseases to genetic variants. These tools allow clinicians and researchers to search across previously siloed databases, clinics, and laboratories and access data about the potential genetic underpinnings of undiagnosed rare diseases across international boundaries. But to date there hasn’t been much research on the user experience.
When it comes to breast cancer, Non-Hispanic Black women have a 40% higher mortality rate than Non-Hispanic White women. Additionally, Non-Hispanic Black women have dramatically lower rates of uptake of genetic testing and then, if testing finds variants that would warrant such actions, undergoing prophylactic preventative surgeries.
As cardiovascular disease has many known genetic components, a team of researchers at Baylor College of Medicine created a panel of genes associated with cardiovascular disease they call HeartCare. David Murdock, previously the assistant director of the clinical lab at Baylor College of Medicine’s Human Genome Sequencing Center and now a lab director at Invitae, states “we thought that by looking at genetic causes of cardiovascular disease in an adult population, that could really help us to push forward genetic testing in adults in general”.
On this month’s GenePod, David Murdock and Eric Venner, director of clinical informatics at Baylor College of Medicine’s Human Genome Sequencing Center, discuss results and implications of the HeartCare gene panel testing of over 700 individuals from Baylor cardiology clinics.
Polygenic risk scores (PRS) can be an important tool in breast cancer patients to help stratify individuals into levels of disease risk. The clinical utility of PRS is still being evaluated, but what hasn't yet been evaluated is how to communicate such results to patients, and how they respond to their PRS scores.
On this month’s GenePod, Tatiane Yanes, a post-doctoral researcher at the University of Queensland and a genetic counselor at the Queensland Children’s Hospital, discusses how a team of researchers surveyed an existing pool of patients that had undergone genetic testing for breast cancer. “We're really just trying to get an understanding of how someone might respond to receiving this information, and what sort of decisions they might make around their breast cancer risk management”, said Yanes.
Researchers are still laying the groundwork in the search for therapeutics that target the mechanism for genetic disorders leading to new treatments. On this month’s GenePod, authors of two recently published articles in Genetics in Medicine discuss where trials for such molecules are succeeding and where there is still more research to be done to determine the efficacy and safety of new treatments.
Ravi Savarirayan, professor of genetics at the Murdoch Children’s Research Institute discusses the long-term study of vosoritide – the first drug to be approved to treat achondroplasia in Europe with ongoing FDA review in the United States.
Maxime Luu, at the University Hospital of Dijon, explains why a trial to treat PIK3CA overgrowth spectrum (PROS) with the breast cancer drug taselisib was halted and, nevertheless, how this promising line of research may proceed in the future.
Congenital anomalies (CA), developmental delay (DD), and intellectual disability (ID) are among the most common indicators in children that lead to genetic testing. Identification of an underlying diagnosis for CA or DD/ID can be consequential to care management and long-term prognosis for the child. But there has been no evidence-based guideline for clinicians to refer to that supports the use of exome or genome sequencing as a first-line or second-line test for the evaluation of pediatric patients with CA or DD/ID.
On this month’s GenePod, Fuki Hisama, MD, FACMG, FAAN and Murugu Manickam, MD, FACMG, who co-chaired the American College of Medical Genetics and Genomics (ACMG) evidence-based work group, discuss how a team of experts was brought together to provide the ACMG’s first ever evidence-based clinical guideline. This guideline lays out clear recommendations for use of exome or genome sequencing in clinical care to optimize outcomes for pediatric patients with CA or DD/ID. “In a way, this model of an evidence-based guideline is creating the standard and a template for future studies” says Dr. Manickam.
Identifying the underlying genetic cause of kidney failure in patients awaiting transplant can impact donor choice and lead to changes in management and treatment. On this month’s GenePod, Eva Schrezenmeier at Charité-Universitätsmedizin Berlin and Carsten Bergmann at Medizinische Genetik Mainz and University Hospital Freiburg, discuss how genetic testing can identify a diagnosis for patients with kidney failure who are waitlisted for a kidney transplant.
While Fragile X syndrome is the most common cause of inherited intellectual disability, it is still underdiagnosed in the general population. As the phenotype may be subtle, the diagnostic pathway can take years. In addition to this, the syndrome is accompanied by many secondary health conditions — the full spectrum of which are not entirely understood by medical practitioners — adding to the burden of care for patients and families.
On this month’s GenePod, Arezoo Movaghar, PhD, a post-doc in the Waisman Center at the University of Wisconsin-Madison, and Marsha Mailick, PhD, emeritus vice chancellor for research and graduate education at the University of Wisconsin-Madison, discuss the use of artificial intelligence to both identify the prevalence and severity of secondary medical conditions and to accurately diagnose patients years in advance of a typical clinical diagnosis.
Universal newborn screening has been successful at improving treatment and decreasing morbidity and mortality for a number of childhood diseases. Recently, a team of researchers investigated the utility of newborn screening for rare genetic pediatric cancer syndromes. Knowing whether a newborn has a genetic variant strongly associated with pediatric cancer predisposition syndromes can potentially lead to focused surveillance of these infants, improved management, better health outcomes, and may even be cost-effective. On this month’s GenePod, Lisa Diller, MD, professor of pediatrics at Harvard Medical School and vice chair of pediatric oncology at the Dana Farber Cancer Institute, and Jennifer Yeh, PhD, assistant professor of pediatrics at Harvard Medical School, discuss their model-based universal screening program to answer questions about potential benefits, costs, and risks of universal newborn screening for pediatric cancer predisposition syndromes.
All too often, genomic testing in patients with undiagnosed disorders results in the finding of variants of unknown significance (VUS). This leaves the health-care provider and patient in a quandary, not knowing whether that variant is disease causing or not. On this month’s GenePod, Bekim Sadikovic, PhD, director of the Clinical Genomic Center and head of the molecular diagnostics program at Canada’s Western University, discusses the implementation of genomic DNA methylation testing in patients with rare disorders – a diagnostic tool that may help sort out the impact of VUS by identifying the signals of DNA methylation.
A lack of research on how diverse communities experience genomic medicine and integrate genetic knowledge into their understanding of and decision making around health care has led to disparities in access and utilization of genomic medicine among minority populations. “The data that's been available historically all points in the direction of suggesting that there's going to be substantial hesitance among patients in taking up new forms of genetic testing and that hesitance is rooted in historical worries”, states Dr. Richard Sharp, director of the Biomedical Ethics Research Program at the Mayo Clinic in Rochester, Minnesota.
On this month’s GenePod, Dr. Sharp and Valentina Hernandez, director of integrated nutrition services and collaborative research for Mountain Park Health Center discuss the results of a survey of both Latinx and non-Latinx patients that assessed their decision to pursue genomic risk evaluation in an effort to address this research gap. Tune in!
The field of medical genetics and genomics has a complex and troubling history vis-a-vis racist ideologies—Carl Linnaeus divided humanity into four “varieties” and Charles Darwin saw humans as genetically distinct races. And, although the field has come a long way since its beginnings, systemic racism lingers in its institutions and practices. On this month’s GenePod, Genetics in Medicine editors Kyle Brothers, MD, PhD, Robin Bennett, MS, CGC, and Mildred Cho, PhD, discuss the work that must be done to start addressing the eradication of systemic racism from scientific publishing. The authors propose eight principles that are both scientifically grounded and anti-racist in an effort to provide a foundation for enlightened policy development by publishers and editorial boards in genetics and genomics. Tune in!
In newborn screening tests, after a first-tier abnormal screening result, single gene or multi-gene testing panels are often utilized as second- or third-tier tests. However, the technologies typically employed today do not scale well and this is a real problem for the high-volume rapid throughput nature of newborn screening labs. On this month’s GenePod, Drs. Nicole Ruiz-Shultz and Andreas Rohrwasser of the Utah Public Health Laboratory discuss how they tested targeted exome sequencing, which focuses analysis on the most relevant subset of genes. Tune in!
While newborn screening is gradually expanding in many states in the U.S. and other countries to include some members of a class of diseases known as lysosomal storage diseases (LSD), there has yet to be a screening test available for one LSD called metachromatic leukodystrophy (MLD). MLD is a rare neurogenetic condition that is often fatal and there is currently no widely available approved treatment. However, there are a number of promising therapies under development in ongoing clinical trials. Michael H. Gelb, PhD, professor of chemistry and biochemistry at the University of Washington, recently turned his attention to developing a newborn screening test for MLD, which he discusses on this month’s GenePod. Based on the results of more than 27,000 newborns screened for this study, Dr. Gelb believes that a newborn screening test for MLD, upon completion of a second unblinded prospective study, could soon become part of the Federal Recommended Uniform Screening Panel. Tune in!
Barth syndrome, an exceedingly rare genetic condition that affects only males, causes heart disease and immune deficiencies–and there’s no known treatment that addresses the cause of the disease. On this month’s GenePod, Hilary Vernon, MD, PhD, associate professor of genetic medicine at Johns Hopkins University School of Medicine, describes a study of elamipretide, a compound already under clinical investigation that, based on its effectiveness in targeting mitochondria, she and her colleagues thought might help their Barth syndrome patients. Based on the results of the study, Dr. Vernon says elamipretide could become the primary treatment for Barth syndrome. Tune in!
Could genome sequencing be used to prospectively identify people at high risk for having a genetic disorder? And, could this enable early multidisciplinary care and avoid life-threatening events? On this month’s GenePod, Bruce D. Gelb, MD, director of the Mindich Child Health and Development Institute at Mount Sinai’s Icahn School of Medicine, describes the genotype-first approach his team took. Dr. Gelb and his team used biobanks to identify individuals with variants likely causing heart conditions associated with RASopathies or Marfan syndrome. The team then went to the electronic health records of those individuals to determine if they had been diagnosed; many had not! Furthermore, identifying individuals by genotype first yielded new insights into their phenotypes. Tune in!
Specialty clinics are an exceptional resource, but research has shown that 95% of those with Down syndrome lack direct access to a Down syndrome specialty clinic. Yet, those with Down syndrome are more likely to be up-to-date with health-care guidelines if their caregivers have access to an online health-care tool. On this month’s GenePod, Brian Skotko, MD, MPP, director of the Down Syndrome Program at MassGeneral Hospital for Children discusses a web-based tool that dramatically improved patients’ likelihood of being up-to-date on Down syndrome health-care guidelines. Tune in!
A history of distrust and skepticism surrounds genetics research for Alaska Native tribes. Not having tribal health organizations engaged with genetics research in a meaningful way means Alaska Native people are missing out on benefits from discoveries that come out of research. On this month’s GenePod, Denise Dillard, PhD, director of research for Southcentral Foundation, a tribal healthcare organization, discusses the goals behind facilitating a workshop between Alaska tribal leadership, biomedical researchers, and representatives from the National Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC). The key takeaways from the workshop build upon ways to overcome barriers and address the need to form more effective partnerships. Tune in!
Genetic and genomic information is a powerful tool in personalized medical care. It is essential for both diagnostic purposes and medical management. But when it comes to genetic test results, electronic health records (EHRs) are generally not searchable or standardized. Tune in to this month’s GenePod, Genetics in Medicine’s monthly podcast, to hear co-authors Dr. Theresa Grebe, a clinical geneticist at Phoenix Children’s Hospital, and Dr. Marc Williams, director emeritus of the Genomic Medicine Institute at Geisinger, discuss ACMG’s recent points to consider statement from the ACMG on the interface of genomic information with the EHR and how to optimize EHRs for genomic medicine.
The COVID-19 pandemic is unprecedented and clinicians have faced correspondingly unprecedented challenges in caring for patients in genetics and metabolic disease clinics who require routine check-ups and ongoing treatments. Yet, in overcoming these challenges, doctors have identified a few boons to patient care that may continue to benefit patients in the long run. Listen in to this month’s GenePod to hear how Dr. Nicola Brunetti-Pierri, a clinician at the Federico II University Hospital in Naples, Italy, and Dr. Elaine Pereira, a clinical geneticist at Columbia University in New York City, two of the areas hardest hit by the pandemic, adapted patient care amid government lock-downs and what silver linings they found.
In this month’s podcast, Genetics in Medicine reached out to members of the genetics research community involved in the global initiatives to identify the genes that cause differences in susceptibility and outcomes to COVID-19: Mark Daly, PhD, director for the Institute of Molecular Medicine Finland and a member of the Broad Institute in Massachusetts, Kári Stefánsson, MD, founder and CEO of deCODE, and our own Deputy Editor, David T. Miller, MD, PhD, a medical geneticist at Boston Children’s Hospital. Together, these three discuss key methods involved in conducting genome-wide studies on a global level to understand differences in SARS-CoV-2 infection rate and severity. The hope is, these efforts will be vital for providing clues to pathways of viral infection and ultimately development of therapeutics and vaccines.
RNA analysis can be an important addition to genetic sequencing in order to improve clinical care and to best understand variants. As clinicians use genomic testing more, the number of identified variants has also ballooned. But, for many variants, it is unknown whether they are pathogenic. The large number of variants of uncertain significance (VUS) can hinder or slow down a diagnosis. On this month’s GenePod, Dr. Diana Baralle, a professor of genomic medicine at the University of Southampton, and a clinician and clinical geneticist at the University Hospital Southampton NHS Foundation Trust, discusses a recent article published in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG) that shows, on a larger scale, how VUS were evaluated using RNA functional studies increasing clinical diagnostic rate and resolving VUS.
A group of more than 130 disorders share a common problem: a glycosylation issue in development where the necessary sugar chains are fully or partly missing from their needed location on protein surfaces. Patients with one of the congenital disorders of glycosylation (CDG) called SLC35A2-CDG are missing galactose, the sugar in milk, on their proteins. Without this sugar chain building block, SLC35A-CDG patients often suffer from severe epilepsy, liver dysfunction and decreased coagulation among other symptoms. Tune in to this month’s GenePod to hear Dr. Eva Morava, a professor of medical genetics at the Mayo Clinic, discuss how moonlighting enzymes and metabolic adaptation from a galactose supplement benefited patients in a small pilot study published in Genetics in Medicine.
Is more better? As the cost of genetic testing plummets, allowing more people to get testing of more genes, researchers and clinicians are asking: who should get tested, and for what? One recent study suggested that all breast cancer patients should get genetic testing. But does the evidence support this approach? In a recent ACMG statement published in Genetics in Medicine (GIM), the statement’s authors weighed the evidence for BRCA1/2 and other germline genetic testing in patients with breast cancer and recommended points for clinicians to consider. On this month’s episode of GenePod, GIM’s monthly podcast, host Cynthia Graber talks with Dr. Tuya Pal, associate director for cancer health disparities at the Vanderbilt University Ingram Cancer Center and first author of ACMG’s recent statement, and Dr. Susan Domchek, director of the Basser Center for BRCA at the University of Pennsylvania and author of a commentary on the ACMG statement, about the evidence, gaps in current knowledge, and how to improve testing rates among high-risk patients.
"Despite all the tools available for the clinical diagnosis of neurodevelopmental disorders, about half remain undiagnosed”, states Dr. Stefan Rentas, first author of a recently published article in GIM. For many patients with neurodevelopmental disorders, a genetic diagnosis doesn't come easy. Genetic testing often comes back negative, even when a Mendelian disorder is very likely, leaving more than half of patients undiagnosed. One explanation is that researchers simply haven't found all the variants that can cause a disorder, but the disorder could also be caused by non-coding regions of the genome that aren't examined with current techniques. That's why Dr. Rentas and his colleagues at the Children's Hospital of Philadelphia turned to RNA sequencing. By looking at gene expression through RNA sequencing, instead of just the genes themselves, abnormalities in the functional output of those genes can be discovered. In this month’s GenePod, host Cynthia Graber chats with Dr. Rentas about how his team successfully diagnosed several of these patients through RNA sequencing, and what a genetic diagnosis really means.
When a variant of unknown significance (VUS) shows up in a genetic test, it's frustrating. Without clinical data backing the pathogenicity of a variant, it is difficult to advise patients. As genetic screening increases, more VUS crop up, and become even harder to classify due to an expanding pool of clinical characteristics of patients. For BRCA1/BRCA2 testing, VUS occur in 2-4% of cases, and the number of VUS that have been identified is roughly equal to the number of pathogenic variants. In a recent publication in GIM, Dr. David Goldgar and his team expanded on their work studying VUS in BRCA1/BRCA2 using clinical genetic tests in 138,000 individuals undergoing genetic testing for hereditary cancer. On this month's GenePod, Dr. Goldgar discusses their new model for predicting pathogenicity of BRCA1/BRCA2 VUS using family history, and the value of grouping similar VUS, rather than studying them individually.
A precision medicine approach has advanced the development of new cancer therapies and researchers who study neurodegenerative diseases would like to replicate that model. Yet, few neurologists recommend genetic testing to patients with neurodegenerative disorders such as Parkinson’s disease. Dr. Roy Alcalay, a neurologist and associate professor at Columbia University Irving Medical Center, and colleagues wanted to discover what’s holding them back.
Although genetic sequencing has aided the diagnosis of many genetic diseases, only about one third of children with unknown or rare genetic diseases end up with a diagnosis after exome sequencing. To help these patients, Stanley Nelson, professor of human genetics at the David Geffen School of Medicine at UCLA, wanted to explore the genome more effectively.