Genetic research in HIE is still in its early stages, but it’s opening the door to potentially transformative advances in both prenatal and postnatal care. And while it may not have all of the answers yet, its insights are building a foundation for supporting HIE families in the future – potentially offering explanations, guiding care, and paving the way for more tailored therapies and interventions that make a difference.
Dr. Christian Parobek, a maternal-fetal-medicine genetics fellow and researcher at Baylor College of Medicine, and Dr. Steven Lazar, a neonatal neurologist at Baylor, recently met with Hope for HIE to shed light on these genetic underpinnings.
Missed the live stream Q&A? No worries. We took notes, and like any good partner, we are willing to share! Read our key takeaways below.
Imagine our entire genetic code as shelves of books—around 20,500 books, to be exact, each representing a different gene. These books collectively make up our “instruction manual” for how the body is supposed to grow, develop, and function. Different genetic tests allow doctors to “browse” this library at various levels:
Chromosomal Microarray is one of the more established tests. It’s like scanning all the shelves to see if any sections are missing, duplicated, or in the wrong order. This test can spot more significant structural changes, such as extra or missing copies of chromosomes, but it doesn’t dive into the more minor details within each gene.
Exome Sequencing is more detailed, involving a close look at each “book” to identify spelling changes or other minor mistakes in individual genes that could impact their function. This level of analysis can uncover tiny but critical changes that might contribute to medical issues.
Whole Genome Sequencing goes even further, combining the functions of both tests to look at the entire library as a whole. Although it was historically costly, technological advances are making this comprehensive option faster and more accessible—even in the NICU—providing answers in days instead of weeks or months.
It’s also important to understand that not all genetic tests provide the same information. Some changes are only present in certain cells or specific parts of the genome, so even a thorough test may not always capture every possible genetic variation.
Genetic tests help us understand the structure and “spelling” of DNA—like examining a book to make sure each page and word is in place. But while these tests tell us if there’s anything unusual about the DNA’s structure, they don’t reveal if the body is actually using or “reading” these instructions. This is where gene expression comes in: it’s the process by which the body decides which genes to “turn on” or “off,” adjusting their activity based on what’s needed. Gene expression controls how much of a specific gene’s product (like a protein) is made, which can influence healing and recovery.
When an injury like HIE occurs, such as when a baby experiences low oxygen levels, the body reacts by altering the activity of certain genes. This is similar to adjusting the volume knob on different genes: some genes are “turned up” to help protect or repair, while others may be “turned down” to conserve energy. This shifting of gene activity is part of the body’s response to and managing the effects of the injury.
This adaptability in gene expression is why genetics alone can’t predict health outcomes completely. Both genes and environmental factors—like an injury—work together to shape how the body responds. It’s the combination of a person’s genetic instructions and how these instructions are adjusted in real-time that helps determine their body’s overall response, resilience, and recovery.
Knowing more about genetics can provide insights and potential clarity for families asking, “Why did this happen?” or “What’s next?”
Certain genetic patterns might help doctors predict who is at a higher risk for developing conditions such as seizures or neurodevelopmental challenges after HIE. This information can guide decisions around early intervention and personalized care.
While HIE can often result from events like placental abruption or low HIE’sn during birth, genetic factors can also play a role. This is why genetic testing is an important recommendation — to see if underlying genetic predispositions might make a baby more susceptible to HIE or influence how they respond to treatment.
Not all babies with the same environmental risk factors go on to develop HIE, and some without any apparent risk factors still receive an HIE diagnosis. Genetics helps bridge this gap in understanding why some children are affected while others are not, giving families a deeper perspective on the condition.
From an OBGYN perspective, tools like fetal monitoring were developed to detect stress in the baby during labor, ideally preventing complications like cerebral palsy and HIE. But while fetal monitoring has been around since the 1970s (and the number of preventative efforts like cesarean sections have risen as a result), the overall rate of HIE has not significantly decreased. It goes to show the potential value of genetics in providing insights where traditional tools may fall short: it might eventually allow doctors to identify at-risk babies even before birth, tailoring care in a way that minimizes risk where possible and prepares for more targeted interventions when needed.
Understanding HIE: Genetics research has identified a handful of conditions that tend to occur alongside HIE, and they fall into two categories: conditions that mimic HIE and conditions that raise the risk of HIE.
Managing HIE: It may be surprising to hear that, in the world of prenatal care, HIE management hasn’t shifted much over the past few decades; most changes in HIE research and care are happening after birth. And one of the most exciting shifts in postnatal HIE care is how genetic testing is now much more accessible than it used to be. Thanks to advancements in testing technology, full-genome scans—which search through each letter of DNA—are now available at a fraction of what they once cost (just a measly 100 million dollars. Yes, you read that right!) Many families today have access to genetic testing for under $2,000 (often with the option of insurance coverage!) This ease of access is changing how doctors approach HIE, allowing them to investigate possible genetic connections much earlier.
Aside from the extra money families can stash away in their wallets, why does this shift in accessibility matter? Well, in the past, genetic testing often started with identifying a child’s symptoms, or “phenotype,” and then checking for specific genetic markers that matched those symptoms. But today, doctors are taking a “genotype-first” approach, testing broadly for genetic variations from the start. This shift means that genetic testing is no longer just about treatment—it’s also about giving families answers, providing peace of mind, and sometimes even alleviating feelings of guilt when families learn that their child’s HIE has a genetic component.
Not to mention that understanding the interplay between genetics and HIE can help parents and providers better predict long-term development, especially regarding cognitive, social, and behavioral outcomes. Before, genetic testing might only be considered if a child showed significant developmental delays beyond what doctors expected based on the initial brain scans or medical history. But now, genetic screening is being offered more proactively to help families understand the potential challenges ahead and, most importantly, create more individualized intervention plans as these children grow.
Dr. Parobek and his research team at Baylor College of Medicine investigated a cohort of 24 children diagnosed with HIE who underwent genome or exome sequencing. They discovered that six of the 24 children had clear genetic diagnoses (25% identification rate for genetic conditions) and that another 25% showed potential genetic indicators, or clues, that might relate to HIE but aren’t classified as definitive diagnoses yet.
A fascinating part of their study involved exploring prenatal or risk factors that might influence the likelihood of a genetic diagnosis. The team hypothesized that cases of unexplained HIE — those without identifiable events like placental abruption or uterine rupture, for example — would show a higher chance of revealing a genetic basis. But their results showed genetic diagnoses in both unexplained and explainable cases.
Understandably, they wondered about these findings until a study from China yielded similar findings that further supports this data. There, researchers analyzed exome sequencing data from 1,500 children with cerebral palsy, categorizing them based on whether they experienced a hypoxic event during labor. Interestingly, the group that had experienced a hypoxic event had a higher rate of genetic diagnoses.
Dr. Parobek is optimistic about the future of research on HIE, particularly regarding genetic factors. He is collaborating with Dr. Lazar on a comprehensive retrospective analysis that includes systematic reviews of existing literature. They are also initiating a prospective study to recruit and sequence families in the NICU whose infants are undergoing cooling therapy for HIE.
They are exploring an important question: which children with HIE should undergo genetic testing? Dr. Lazar suggests that one day, genetic testing could be provided for all infants with an HIE diagnosis to better understand outcomes. However, a key issue is determining whether every child with HIE would benefit from genetic sequencing—even if their HIE appears to have a non-genetic cause—or if there are specific groups who would truly benefit the most. Although data is currently limited, research teams are working on broader, unselected sequencing studies, which could significantly advance our understanding of HIE in the future.
While there isn’t an extensive amount of data yet on the overlap between HIE and genetic factors, there are still resources that offer valuable information and support around the genetic aspects of developmental disabilities and rare neurological conditions.
To watch the full live stream of this Q&A, visit our YouTube channel below, or click on our Key Takeaways for an at-a-glance view of this session!
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