Are there some babies born with HIE that have a genetic condition? Is it really HIE? Are there genetic factors that can make a baby more susceptible to HIE?
The short answers? Yes, often yes (you can have both a genetic condition AND a brain injury) and likely yes.
A decade ago, many HIE families were sent for metabolic testing to rule out mitochondrial disease. 99.9% of our families who reported testing came back negative. However, genetic testing was NOT available widely like it is today. We know so much more than we did a decade ago, and identifying specific genetic mutations can better support families, connect them to specific support, and lead to disease-modifying therapeutics to improve care. Prenatally, there are some researchers looking at genetic influences that may contribute to HIE and perhaps could be identified and interventions implemented to decrease the incidence of HIE.
First, let’s talk about what is a genetic mutation and how genetic influence, expression and damaged genetic pathways can help us learn more about what possibly can lead to HIE and drive therapeutic innovation and intervention.
Genetic mutations are changes in the DNA sequence of an organism’s genome. These alterations can occur spontaneously (de novo) due to errors during DNA replication or can be induced by external factors such as radiation, chemicals, or viruses, or inherited. Mutations can be classified into several types, including point mutations (a change in a single nucleotide), insertions, deletions, and duplications. The effects of genetic mutations can vary widely, from being harmless or even beneficial to causing serious diseases or developmental issues. Mutations can be passed on to offspring if they occur in germ cells (sperm or eggs).
Genetic influence refers to the effect that an organism’s genetic makeup has on its traits and characteristics. This influence is exerted through the expression of genes, which are segments of DNA that code for proteins or regulate other genes. Genetic influence is responsible for inherited traits such as eye color, height, and susceptibility to certain diseases. It also plays a role in complex characteristics like intelligence, behavior, and risk of developing chronic conditions. While genetic influence is a significant factor in determining these traits, it often interacts with environmental factors, resulting in the observed phenotype (the organism’s physical and behavioral traits).
Could HIE damage specific pathways? Some research says yes!
Dr. Shilpa Kadam has discovered that the KCC2 pathway can be responsible for two different outcomes that relate to seizures and epilepsy in HIE:
There are many researchers looking into genetics and influence with HIE. We are excited to start partnering with them and encouraging this research up and down the care continuum to decrease the incidence and impact of HIE, and we have some links to recent published studies, articles and more to share for those who want to dig in!
Do genetics play a part in making a baby more susceptible to HIE?
These researchers wanted to find out more about a cohort of HIE babies who didn’t have a clear presentation of causation of HIE, and see if there were genetic markers that may be at play.
What they wanted to know: How many babies who already had gone through genetic testing for HIE as a rule out had markers. They reviewed 210 charts available meeting the criteria for HIE.
What they found: 28 of the 210 had genetic testing done. Of the 28, 10 of the babies (38% who were tested) had a marker come back for a genetic mutation.
What this means: More research needs to be done to screen genetics and HIE!
HIE is under the umbrella of Neonatal Encephalopathy — the most common cause of NE, but there are others including genetic, metabolic, and congenital brain malformation causes. Genetic testing is becoming more prevalent with Neonatal Encephalopathy, both in the ability to identify babies who truly do not have HIE and families can be directed to appropriate support, and in understanding the influence genetics may have in neonatal HIE causation.
What they wanted to know: How many babies in the HEAL study had genetic or preexisting brain anomalies/congenital issues, since genetic testing has not previously been so widely and accurately available.
What they found: 5% of the cohort of 500 babies had either a genetic or brain anomaly. The babies with these findings had worse neurodevelopmental outcomes than infants with HIE alone.
What this means: Etiology, or cause, is important not only for clinicians and researchers, but for families to understand for not only their own knowledge about their child’s medical information, but for family planning, recurrence probability, appropriate community support and potentially targeted genetic therapeutic interventions that are or may become available.
Researchers studying cooling in India, Sri Lanka and Bangladesh, from the HELIX study took the blood samples and analyzed them against babies in higher income countries to see if the gene expression was different.
What they wanted to know: Why cooling didn’t work for the HELIX trial, and if there was something about the population that was different than other areas in the world.
What they found: Genetic expression was very different in the HELIX population, which led researchers to look at maternal factors in environmental impacts and the nature and timing of HIE may be very different than other populations.
What this means: We could know more why some babies benefit from therapeutic hypothermia and some do not, which leads to better care and interventions developed for different populations.
Can some known genetic variants have an influence and correlation with HIE? Researchers in Croatia did a retrospective study of 279 participants, of which 132 had HIE and looked at the frequency of six tag Single Nucleotide Polymorphisms. What are SNPs? They are a part of genetic coding and these six selected are more of the common ones found like MTHFR, which is a known code for proteins involved in clotting. Others selected are known for regulating blood pressure, and plasticity.
What they wanted to know: Do SNPs have a correlation to HIE brain injury?
What they found: This work showed a correlation to more severe outcomes, and it built off of work that showed babies with HIE with associated SNPs also had a greater likelihood of developing epilepsy.
What this means: More work needs to be done to see if identification early in gestation can drive different monitoring and delivery strategies to decrease the incidence and impact of HIE.
We love to see obstetricians and maternal-fetal medicine clinician-scientists tackling HIE research, and recently connected with Dr. Christian Parobek, lead author on this study to learn more about his current and future research. This study was a case review study of babies who were diagnosed with HIE and also had genetic testing within the first year of birth.
What they wanted to know: How many babies had either a genetic variant present.
What they found: Four babies in the cohort (17%) had a genetic variant or likely variant link to their HIE.
What this means: More research is needed. Many questions remain as many babies are now sent for genetic testing under the umbrella of Neonatal Encephalopathy, but what concerns may lead to that referral likely vary. It’s another piece of evidence that moves towards advocating for all babies with Neonatal Encephalopathy to receive genetic testing with the lowered cost and increased accessibility of testing so we can learn more. (our take, not necessarily the conclusion of the article!)
Researchers out of South Africa, Dr. Michael Pepper et al, have been using the term NESHIE — Neonatal Encephalopathy with Suspected Hypoxic Ischemic Encephalopathy to accurately describe the patient population more broadly, to further understand the various causes and outcomes.
What they want to know: How many babies deemed NESHIE who develop cerebral palsy have a genetic mutation or variant of unknown significance (VUS).
What they found: They built an infrastructure and database based off of already published research and collected data from their sources that can be searchable and narrow down focus to genes they believe have the strongest correlation to a risk factor to develop HIE and CP.
In total, 12 genes met the prioritisation criteria. Of the prioritised genes, the angiotensinogen (AGT), AP4B1, CARD8, CAT, IL6, IL10, IL1B, MTHFR, NOS3, OLIG2 and TNF genes had statistically significant associations with NESHIE or CP (as result of NESHIE). Although variants in COL4A1 have not been significantly associated with NESHIE or CP as a consequence of NESHIE, the COL4A1 gene was prioritised since (i) the gene has prior associations with cerebral ischemia and tissue ischemia disease phenotypes; and (ii) variants in the gene have been reported in patients with CP (as a result of birth asphyxia)
https://www.sciencedirect.com/science/article/pii/S0888754322002531
What this means: Prenatal screening may lead to better identification of what babies are most at risk, which can lead to interventions and better prenatal and birth care.
Here are a few additional resources to understand genetics with educational and support information:
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