GenePod: Genetics in Medicine’s Podcast

Kidney stone disease affects approximately one in 11 people over their lifetime and recent research has shown that rare genetic variants contribute to 15 percent cases. That fraction is even higher among children. A team of researchers at Boston Children’s Hospital had reason to believe there might be additional genetic links not yet identified. Amar Majmundar, MD, PhD, a pediatric nephrologist and researcher, joins GenePod to discuss the results of a recent study identifying the variant OXGR1 as a novel candidate disease gene for kidney stone disease, which he and his colleagues published in the journal Genetics in Medicine.

Epilepsy is one of the most common neurological diseases, with more than 50 million people affected worldwide and Sub-Saharan Africa carries the highest burden of the disease. However, most of the research on epilepsy, and the genetic variants that lead to developmental and epileptic encephalopathies, has been conducted in wealthier, resource-rich regions. So, a team of researchers recently conducted a study on children in South Africa whose phenotypic profile suggested there could be a genetic component; the results of that study, as well as the recommendations that arose from it, were recently published in the journal Genetics in Medicine. Jo Wilmshurst, MD, child neurologist at Red Cross War Memorial Children’s Hospital and a professor at the University of Cape Town, and Gemma Carvill, PhD, geneticist and assistant professor at Northwestern University in the department of neurology, joined GenePod to discuss the results of the study and the implications for care in a resource-limited setting.

The Health Information National Trends Survey, or HINTS, takes a nationally representative look at the public awareness and use of health-related information. The last time genetics questions were included in HINTS was in 2017, and at that point, just over half of Americans were aware of genetic testing. In a recent study published in the journal Genetics in Medicine, a team of researchers analyzed data from the 2020 HINTS survey, which once again included genetics-related questions. Leah Mechanic, MPH, PhD, program director at the National Cancer Institute, and Kathy Helzlsouer, MD, associate director in the epidemiology and genetics research program at the National Cancer Institute, join GenePod to discuss the results of the analysis.

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!