DNA Today: A Genetics Podcast

What happens when traditional genetic testing leaves patients and families without answers? Emerging technologies like optical genome mapping (OGM) and long-read sequencing are expanding what laboratories can detect, from complex structural variants to difficult-to-analyze repetitive regions of the genome. These advances are already changing clinical testing strategies and helping uncover diagnoses that previously remained out of reach. In this episode, we welcome back Dr. Nikhil Sahajpal, Assistant Laboratory Director at Greenwood Genetic Center (GGC), who previously joined us in Episode 362 to introduce optical genome mapping. Now, nearly two years after GGC began offering OGM clinically, Dr. Sahajpal shares how the technology is being integrated into rare disease diagnostics, including additional diagnostic findings in at least 5% of previously unsolved cases. The conversation takes a closer look at facioscapulohumeral muscular dystrophy (FSHD), a genetically complex condition involving D4Z4 repeat contractions, epigenetic changes, and inappropriate DUX4 expression. Dr. Sahajpal explains how OGM and short-read sequencing can work together to distinguish FSHD1 from FSHD2, and why the laboratory is evaluating long-read sequencing as a potential way to streamline this testing. We also explore targeted applications of OGM and long-read sequencing, including clarifying DMD duplications, mapping structural variant breakpoints, and determining whether variants are in cis or trans. Finally, Dr. Sahajpal discusses where long-read genome sequencing fits into the rare disease diagnostic workflow and whether a more comprehensive, unified genetic test could eventually reduce the need for multiple testing platforms. Episode Discussion Topics How optical genome mapping compares with karyotyping, FISH, and chromosomal microarray Greenwood Genetic Center's clinical experience with OGM and its additional diagnostic yield in previously unsolved rare disease cases When OGM may serve as a reflex test following negative genome sequencing The genetics of FSHD1, including D4Z4 repeat contractions, permissive haplotypes, and DUX4 expression Why chromosome 4 and chromosome 10 repeat regions complicate FSHD testing How OGM and short-read sequencing contribute to distinguishing FSHD1 and FSHD2 The potential for long-read sequencing to assess repeat size, sequence variants, and DNA methylation When long-read genome sequencing may be appropriate for patients with broad or nonspecific phenotypes How targeted OGM can clarify DMD duplications and change carrier screening interpretation Using targeted long-read sequencing to phase variants in recessive conditions without parental samples The limitations of phenotype-driven variant analysis and the future of comprehensive genomic testing Resources & Links Greenwood Genetic Center OGM Complete OGM Targeted Facioscapulohumeral Muscular Dystrophy Type 2 (FSHD2) NGS Panel FSHD1 Long-read Sequencing-Trio Analysis Long-read Sequencing-Targeted Analysis Sahajpal Completes Laboratory Fellowship at GGC and Joins Faculty Sahajpal NS, Mondal AK, Singh H, Vashisht A, Ananth S, Saul D, Hastie AR, Hilton B, DuPont BR, Savage NM, Kota V, Chaubey A, Cortes JE, Kolhe R. Clinical Utility of Optical Genome Mapping and 523-Gene Next Generation Sequencing Panel for Comprehensive Evaluation of Myeloid Cancers. Cancers (Basel). 2023 Jun 16;15(12):3214. doi: 10.3390/cancers15123214. PMID: 37370824; PMCID: PMC10296552. Relevant DNA Today Podcast Episode #362 Optical Genome Mapping: Detecting Structural Variants Missed by Traditional Tests (with guest Dr. Nikhil Sahajpal) #279 Reflecting on 50 Years of Greenwood Genetic Center #183 Dr. Miga and Dr. Phillippy on the Telomere to Telomere Consortium #182 Eric Green on the Complete Human Genome Project #145 Greenwood Genetic Center on Epigenetics Connect with DNA Today: You never have to wait long for a new episode of DNA Today, we release episodes every Frida

How can variants in the same gene cause life-threatening disease in infancy for some individuals, while others experience mild symptoms or remain asymptomatic? Hypophosphatasia (HPP) challenges traditional expectations about genetic inheritance, with both autosomal dominant and autosomal recessive forms and a remarkably broad spectrum of clinical presentations. In this episode, recorded in person in Nashville, our guest is Dr. Kathryn Dahir, Professor of Medicine in the Division of Diabetes, Endocrinology, and Metabolism at Vanderbilt University Medical Center and Director of the Program for Metabolic Bone Disorders. Drawing on decades of experience caring for patients with rare skeletal conditions, Dr. Dahir explores the complex genetics of HPP and why understanding a patient's clinical presentation is just as important as interpreting their genetic test results. The conversation begins with a patient case that challenged Dr. Dahir's understanding of HPP. Initially treated for osteoporosis, the patient experienced recurrent fractures and worsening symptoms despite treatment. Further investigation revealed impaired bone mineralization, low alkaline phosphatase (ALP), and a single ALPL variant, illustrating how individuals with one affected copy of the gene can experience significant disease. Dr. Dahir explains how the ALPL gene encodes tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme essential for healthy bone mineralization, and how disruption of its activity contributes to the manifestations of HPP. We explore the differences between autosomal dominant and autosomal recessive inheritance, the challenges of predicting disease severity from genetic testing alone, and why even relatives carrying the same ALPL variant may have very different symptoms. Dr. Dahir discusses the importance of identifying variants in cis or trans, recognizing deletions and duplications, evaluating variants of uncertain significance, and considering how genetic modifiers, environmental exposures, and coexisting conditions can influence a patient's presentation. Finally, we discuss the evolving landscape of HPP genetic testing, including the importance of longitudinal follow-up, resources such as the global ALPL variant database, and ongoing efforts to improve variant classification. As genomic testing becomes increasingly accessible, this conversation highlights both its potential to improve rare disease diagnosis and the limitations of using genetics alone to predict an individual's future health. Episode Discussion Topics Dr. Dahir's clinical experience treating HPP and other rare metabolic bone disorders at Vanderbilt University Medical Center Why genetic testing must be interpreted alongside clinical symptoms, biochemical findings, and patient history A patient case illustrating how HPP can be mistaken for osteoporosis and why low alkaline phosphatase is an important diagnostic clue How the ALPL gene and tissue-nonspecific alkaline phosphatase (TNSALP) regulate bone mineralization The differences between autosomal dominant and autosomal recessive HPP and the challenges of distinguishing affected individuals from asymptomatic carriers Why genotype-phenotype correlations in HPP are complex, even among family members with the same genetic variant The importance of determining whether variants are in cis or trans and identifying deletions or duplications that some testing platforms may miss How modifier genes, epigenetics, medication exposures, and coexisting medical conditions may influence HPP symptoms and severity Interpreting variants of uncertain significance and the importance of genetic counseling, variant reclassification, and long-term follow-up The role of the global ALPL variant database in improving classification and understanding the clinical significance of genetic variants Future opportunities to identify protective genetic factors and improve predictions of disease progression About the HPP Series This episode

For the third year in a row, DNA Today is bringing you inside the American Society of Human Genetics (ASHG) Annual Meeting, and this year, we've taken our genetics coverage international! We're reporting from beautiful Montréal, Canada, where thousands of geneticists, researchers, clinicians, and industry leaders gathered to share the latest breakthroughs shaping the future of genomics. From cutting-edge technologies to big questions about the future of genetic medicine, there's no shortage of exciting science to unpack. And don't worry, we're bringing you all the highlights, no passport required, eh? In this episode, host Kira Dineen takes you behind the scenes of ASHG 2026 through two special segments recorded at the conference. First, we stop by the Nabsys booth to chat with Founder and CEO Barrett Bready, MD, about how Electronic Genome Mapping (EGM) is advancing our ability to detect structural variants. We explore how the technology compares with traditional approaches, its emerging applications in hematologic malignancies, and the latest research Nabsys is showcasing at ASHG. For our second segment, we're live on location! DNA Today teamed up with Wiley's Advanced Portfolio to co-host a special brunch featuring a live podcast recording right from the conference. With breakfast on the table and big questions on the menu, Kira moderated a conversation with leading genetics researchers and publishing experts about the discoveries, challenges, and opportunities shaping the field. From translating genetic findings into new therapies and harnessing AI to accelerate research to fostering interdisciplinary collaboration and rethinking the role of scientific publishing, this discussion goes beyond the conference presentations to explore where genetics is headed next. Whether you joined us in Montréal or are experiencing the conference from afar, consider this your front-row seat to some of the conversations shaping the future of genetics. We're serving up fresh science with a side of maple syrup, because when it comes to genetics, there's always more to discover, eh? Nabsys Segment Guest Barrett Bready, MD is Founder and CEO of Nabsys. He is passionate about the impact that advanced technology can have on the understanding of disease as well as on its diagnosis and treatment. He has raised $150 million to realize a new way of analyzing DNA that uses proprietary solid-state electronic nanodetectors to analyze very long molecules, with an initial focus on genomic structural variation. Barrett is an adjunct professor at Brown University where he lectures on the rapidly evolving business of life sciences. He serves as a commissioner of the I-195 Redevelopment District Commission, a major land redevelopment initiative in downtown Providence, RI with a focus on life sciences and other high-technology sectors. He has received numerous awards including, in 2011, Rhode Island Innovator of the Year, and in 2018, a career achievement award from the Warren Alpert Medical School of Brown University. Barrett graduated from the highly competitive Program in Liberal Medical Education (PLME) at Brown University where he received an M.D. and an Sc.B. in Physics and won the undergraduate physics award (the Lindsay Prize) and the Galletti Prize for physics in medicine. Nabsys Discussion Topics ASHG 2026 conference highlights and a presentation on electronic genome mapping (EGM) in hematologic malignancies Why genomic structural variants matter in cancer and rare disease How traditional sequencing and cytogenetic approaches may leave gaps in detecting structural variation Nabsys’ electronic genome mapping as a high-resolution, top-down approach to studying genome structure How EGM uses electrical detection to read sequence-specific tags on long DNA molecules Identifying deletions, insertions, inversions, and translocations by comparing tag patterns How EGM relates to traditional cytogenetic methods such as FISH and karyotyping The nan

CRISPR has carried enormous promise since scientists first realized its potential to edit the human genome, but it has also raised some of the biggest ethical questions in modern genetics. In this episode, Kira Dineen sits down with Dr. Kiran Musunuru to trace the evolution of human gene editing, beginning with the controversial 2018 announcement that scientist He Jiankui had used CRISPR to edit human embryos in China, resulting in the birth of the world’s first gene-edited babies. The experiment, which targeted the CCR5 gene in an attempt to reduce susceptibility to HIV, sparked international condemnation and intensified debate over germline genome editing, where genetic changes could potentially be passed on to future generations. From there, the conversation shifts to a dramatically different application of CRISPR: treating serious genetic disease in an individual patient. Dr. Musunuru shares the remarkable story of Baby KJ, who was born with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency and became the first patient to receive a personalized CRISPR-based therapy designed specifically for his genetic variant. The team developed KJ’s customized base-editing treatment in approximately six months, moving from identification of his variant through preclinical testing, manufacturing, regulatory review, and ultimately treatment. Dr. Musunuru explains how KJ’s therapy works, what researchers have learned from his response so far, and whether his case could establish a new pathway for treating patients with ultra-rare genetic conditions who may never fit into a traditional drug-development model. This interview was recorded in person at AGBT Precision Health in Coronado, California, we caught up with Dr. Musunuru after a presentation. Episode Discussion Topics: The 2018 announcement of the world’s first CRISPR-edited babies in China Why He Jiankui’s experiment targeting the CCR5 gene sparked global scientific and ethical backlash The difference between editing embryos and germline cells versus editing somatic cells in a patient What the CRISPR babies controversy taught the scientific community about oversight, regulation, and responsible use of gene-editing technology How the field of CRISPR medicine has evolved since 2018 How naturally occurring PCSK9 variants helped reveal a powerful target for lowering LDL cholesterol and preventing cardiovascular disease Using CRISPR base editing to permanently turn down PCSK9 activity in the liver as a potential one-time treatment for high cholesterol The development of PCSK9 gene-editing therapies for patients with familial hypercholesterolemia and premature coronary artery disease The possibility of moving cardiovascular care from lifelong medications to durable, one-time genetic treatments How cardiovascular gene editing helped pave the way for applying similar base-editing technology to rare diseases like Baby KJ’s CPS1 deficiency What CPS1 deficiency is and why it can become life-threatening shortly after birth How Baby KJ’s diagnosis created an opportunity to pursue a personalized gene-editing treatment Why KJ’s specific genetic variant was a candidate for base editing How base editing differs from traditional CRISPR approaches that make double-stranded breaks in DNA Developing a gene-editing therapy specifically for a single patient Delivering the gene editor to liver cells using lipid nanoparticles Why the liver is an especially promising target for in vivo gene-editing therapies The collaboration between researchers, clinicians, biotechnology companies, regulators, and KJ’s family that made the treatment possible Navigating FDA review for a therapy that had never previously been given to a human Why KJ received multiple doses of the therapy Early signs that the treatment was having an effect, including increased dietary protein tolerance and reduced dependence on nitrogen-scavenging medication Why researchers are careful not to describe KJ’s treatment as a cur

Please note this episode is only available on our website, DNAToday.com under Episode 415, and access is limited to those in the United States. In just a few years, achondroplasia treatment has expanded from no approved precision medicines to multiple approaches targeting the condition’s underlying biology. In this episode, we continue our conversation with Dr. Ravi Savarirayan, a global leader in skeletal dysplasia care and a lead investigator across multiple achondroplasia clinical development programs. Dr. Savarirayan previously joined us on Episode 401, where we explored the first approved precision treatment for achondroplasia and international guidance for its use. This time, we take a broader look at the rapidly evolving achondroplasia treatment landscape, including how different therapeutic approaches target FGFR3 signaling, how researchers interpret clinical trial outcomes, and what results from the Phase 3 PROPEL 3 study of investigational infigratinib could mean for children and families. We also discuss why treatments cannot be reliably compared using results from separate clinical trials, the importance of studying outcomes beyond growth, and the questions that remain about long-term safety, functional benefits, treatment selection, and switching therapies. Thank you to BridgeBio for sponsoring this episode. Episode Discussion Topics How the achondroplasia treatment landscape has evolved in the last seven years How achondroplasia affects more than height How current and investigational therapies target FGFR3 signaling in different ways What annualized growth velocity, height Z-scores, and body proportionality reveal in clinical trials Key findings from the Phase 3 PROPEL 3 study of investigational infigratinib What researchers can and cannot yet predict about final adult height based on current data Why body proportionality may be an important clinical and functional outcome How researchers are evaluating potential effects on mobility, reach, independence, and daily activities The long-term safety questions that remain when treatment begins in childhood Why results from separate achondroplasia trials should not be compared directly How families and healthcare providers can weigh treatment benefits, risks, administration, and personal goals What is being studied in hypochondroplasia and other conditions involving overactive FGFR3 signaling Our Guest: Dr. Ravi Savarirayan Ravi Savarirayan is consultant clinical geneticist at Victorian Clinical Genetics Services, Professorial fellow at the University of Melbourne, and Group leader (Molecular Therapies at Murdoch Children’s Research Institute, Victoria, Australia. Professor Savarirayan received his MBBS from the University of Adelaide, Australia in 1990 and became a Fellow of the Royal Australasian College of Physicians in 1997. He was certified as a specialist in Clinical Genetics by the Human Genetics Society of Australasia in 1998 and was awarded his Doctor of Medicine from the University of Melbourne in 2004. He was awarded the Fulbright Professional Scholarship for Australia in 1998, and took this up at University of California, Los Angeles (UCLA). Professor Savarirayan’s primary research focus is on inherited disorders of the skeleton causing short stature, arthritis, and osteoporosis. He has published over 230 peer-reviewed articles and received over $35M in research funding, collaborating with researchers from 40 countries. His current clinical trial activities are pioneering disruptive new therapies for the treatment of genetic disorders. He was the global lead investigator of the clinical development program that identified vosoritide as the first precision therapy for children with achondroplasia. He was recently named one of the 30 “Brilliant minds” of the Murdoch Children’s Research Institute over the past 30 years, was awarded the Institute’s research excellence award in 2020, and is an NHMRC Leadership Fellow. Resources BridgeBio Acho