In this short video, Maternal-Fetal Medicine and Genetics specialist, Dr. Teresa Sparks, MD, MAS, presents a recently published UCSF study of non-immune hydrops fetalis (NIHF) cases. The findings highlight the utility of prenatal exome sequencing for establishing a genetic diagnosis and optimizing the approaches to prenatal management, postnatal care, and patient counseling.
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My name is Teresa Sparks. I'm a specialist in maternal fetal medicine in clinical genetics at UCSF. And today we'll be talking about a fetal condition called non immune high drops. So in terms of the outline for today, we'll first talk about what is non immune high drops. What do we know about the different causes of high drops? How our research at UCSF is illuminating the full range of genetic diseases underlying high drops. And then moving forward thinking about how we can redefine our approach to prenatal diagnosis and care for non immune high drops. Non immune high drops affects approximately one in 1700 to 1 in 3000 pregnancies. Traditionally, non immune high drops is defined by two or more abnormal fetal fluid collections, Those that you say listed here. Those include pericardial effusion, which is fluid around the heart, pleural effusion, which is fluid around the fetal lungs, asides fluid in the abdomen and or skin edema. However, there is also evidence that earlier onset fluid collections, such as increased neutral translucency or cystic high drama in the first trimester of the pregnancy can also either evolve into high drops or the same genetic conditions can present with those early onset fluid collections or later onset traditional high drops. Non immune high drops also carries high risk of stillbirth, preterm birth, neonatal morbidity and mortality, as well as morbidity for the woman as well. Before we continue forward. It's important to think about why should we understand not immune high drops and why should we study this dis condition? The majority of cases remain of unknown ideology, which is problematic from the perspective of the obstetrician managing the pregnancy and the neonatologist expecting to provide care for that neo Nate. There's wide genetic heterogeneity in terms of the underlying diseases that can present in the same way with fluid overload of the fetus and there are very high risks of poor outcomes and these risks importantly, very widely by the underlying disease. So, again, the earlier we can make a diagnosis of the true underlying cause of the non immune high drops, the better we can do in terms of managing the pregnancy, informing the patient in front of us about what to expect for that pregnancy, Making management decisions during the pregnancy and anticipating the neonatal needs immediately after birth. Why does a diagnosis matter as I've alluded to? The ultimate prognosis varies widely according to the underlying genetic ideology of the non immune high drops For some conditions, there are established or emerging treatments that are available and prenatal management may differ substantially by the underlying ideology. Some examples of those include that some genetic diseases can lead to severe cognitive impairment and early death, while others are more mild prompt neonatal treatment can improve the outcome for some of these diseases, such as those that respond to enzyme replacement therapy. And obstetricians can look specifically for the complications of a genetic disease, particularly coexisting birth defects and other risk to the pregnancy. When non immune high drops is diagnosed during the pregnancy, we think broadly about the range of potential causes that include genetic abnormalities, as well as environmental exposures such as viruses. Standard tests that we apply from a genetic perspective too, try to achieve a diagnosis are the more traditional carry a type, which has been used for decades in the setting of prenatal diagnosis, as well as chromosomal micro array, which was more recently introduced, carry a type looks broadly at the chromosomes as you see on the left side of the picture. To understand if there are imbalances and chromosomal micro array can look at a finer level to see if there are smaller imbalances than a carry A type is able to detect. However, neither one of these testing modalities is able to look at the letter by letter sequence of the gene to see if there's a misspelling somewhere in the genome exam. Sequencing is a relatively new technology that has been used in the post natal setting now for several years and has been more recently introduced in the prenatal setting for diagnostic abilities, exam sequencing focuses on the protein coding regions of the genome, which are the exons that you see here That amounts to approximately 20,000 genes in the body. When applied to in other studies, looking at all types of fetal anomalies, exam sequencing is able to detect a single gene disorder that explains the underlying anomaly and approximately 8-20% of cases. So it's a very promising and emerging technology. So, knowing the limitations of our standard of care tests in the prenatal setting for reaching a diagnosis in cases of fetal anomalies and specifically with non immune high drops. It's important to dive deeper and think about the underlying ideologies that were not able to pick up with our existing technologies. Our group at U. C. S. F. Is focused on understanding much more detail about what causes non immune high drops. As you see here, the acronym for our study is entitled high drops, which is high drops, diagnosing and redefining outcomes with precision studies and the goals of our group or to identify genetic diseases underlying non immune high drops and develop more targeted and novel approaches to prenatal care and in utero treatment based on the underlying specific diagnosis. The first of our studies was published last month in the new England Journal of Medicine and over the next few slides, I'll describe the findings of our study. The aims of our study were first to establish the diagnostic yield of exam sequencing for single gene diseases in unexplained non immune high drops, feet, Alice cases, and secondly, to describe this spectrum of underlying genetic disease. We enrolled participants across 19 months during years, 2018: 2020. The inclusion criteria for our study are those that you see listed here. Those are increased neutral translucency, cystic hague Roma Besides pleural effusion, pericardial effusion and or skin edema in the fetus. We also required that a non diagnostic result was achieved using carry a type or micro array Prior to enrolment in the study exclusion criteria were Allah immunization hi drops resulting from antibodies in the maternal blood, clear evidence of a viral infection or twin twin transfusion syndrome. Because those results in high drops from very different mechanisms. The primary outcome of our study was the diagnostic yield of exam sequencing for detecting pathogenic or likely pathogenic genetic variants in unexplained non immune high drops cases. Secondary outcomes were the percentage of cases associated with specific genetic diseases and the proportion of variants that were inherited. We enrolled participants from all five sites of the University of California fetal maternal consortium which include U. C. San Francisco, UC Davis, UC Irvine, UC Los Angeles and U. C. San Diego. In addition due to the relatively rare prevalence of non immune high drops, we also accepted referrals from anywhere in the United States. The exile in sequencing for our study was performed through the UCSF genomic medicine laboratory. For each case, a multi disciplinary panel review occurred for each genetic variant found that included that input from bio informatics shins, geneticists, pathologists, parapsychologist, pediatricians, bioethicists and many other specialists. This review included detailed information about the phenotype, meaning the physical features and the developmental features of each case. And information from pathology examinations were available because this information is critical to accurate interpretation of genetic variants found through exam sequencing trio exam sequencing was performed in the majority of cases in our study. This means that samples were included from each biologic parent in addition to the fetus and the samples from the parents were used as reference in order to compare and understand the inheritance pattern of any variants that were inherited genetic variants were categorized as pathogenic, likely pathogenic or a variant of uncertain significance, according to the criteria as published by the American College of Medical Genetics and genomics. Finally, pathogenic and likely pathogenic variants were considered diagnostic for the purpose of this study. In total, we enrolled 127 unexplained non immune high drops cases. In our study. In 29% of these, we identified a genetic disease through trio exam sequencing. Among the cases in which a diagnostic variant was identified, the most common category of genetic disease were the recipe. These, as you see here in the yellow portion of the pie the recipe. These are a category of disorders that affect a cell signaling pathway and can lead to birth defects, learning problems and differences in appearance after birth. Also common were inborn errors of metabolism and disorders of many systems, including musculoskeletal lymphatic neurodevelopmental cardiovascular Hemet to logic and many others. Examples of genetic diseases that we identified within each of those pieces of the pie from the previous screen include those that are listed here. These are all single gene disorders. And again, none of these would have been identified with standard genetic testing. And now thinking about the diagnostic yield of exam sequencing according to the type of abnormal fluid within the fetus. We saw that the highest yield of exam sequencing was for those cases that had two or more abnormal fluid collections, and also for those cases that presented early on in the first trimester with an increased nukul translucency, or cystic kigoma that also went on to develop additional fluid collections or had concurrent congenital anomalies. The lowest deals, although not insignificant, refer the cases with a single abnormal fetal fluid collection such as isolated asides and then also for cases of an isolated increased nukul translucency or cystic high drama with no other abnormal features. Considering the inheritance patterns of the cases with a diagnostic variant identified. The majority of cases were autism, A dominant, as you see in the blue portion of the pie. About a quarter of cases were autism a recessive and then a very small percentage where each X linked recessive and one that was unknown due to inherent limitations of the sequencing technology. And thinking further about the inheritance patterns among the cases that were autism, all dominant as you see on the left half of the graph, the large majority of them were de novo, meaning that they were not inherited from a parent and occurred sporadically in the fetus And then 36% of the autism a dominant variants were novel, meaning that they had not previously been reported in the literature or in genomic databases. In contrast for the artisanal recessive variants as displayed on the right portion of the graph, you see that a very small percentage occurred de novo, meaning that most of them were inherited from a carrier parent and that the vast majority of these were novel and have not previously been reported. And so what we've learned through this study is that despite a similar prenatal phenotype with fluid overload of the fetus, that can happen really at any point in gestation. There's a very wide range in terms of the underlying diagnoses and importantly, the ultimate post natal prognosis for each of these conditions is very different and affects the counseling that we provide to our patients, and the care that we deliver substantially. Another important piece is that the diagnostic yield that we saw through exam sequencing for non immune high drops specifically is much higher than seeing with other studies of all types of fetal anomalies, which highlights the burden of single gene disorders for non immune high drops. Specifically, our research supports the use of exam sequencing for non immune high drops cases that are not explained by standard genetic testing. It also drives home the important points about how we need to focus our prenatal diagnosis and care according to the true underlying diagnosis rather than the manifestation of simply fluid overload. We might, for example, manage a pregnancy differently. With antenatal surveillance, ultrasounds, MRI antenatal testing and other decision points. We might plan delivery different depending on the underlying diagnosis. We could arrange for prenatal consults and other preparations ahead of time to optimize the post natal care that we deliver to these neon eights for some genetic diseases. Their existing interventions in the prenatal setting, such as for cases of hereditary anemia, says, where we might surveil to see if intra uterine transfusions become indicated. Our recurrent risk counseling, meaning our counseling about the chance of this happening again in a future pregnancy is very different depending on the underlying genetic cause. In some cases it's as, it's as small as 1-2%, and in other cases it's as high as 50%. And then finally, understanding the true underlying genetic disease, paves the way for the development and application of novel in utero treatments that are on the horizon. Our group is very focused on continuing this research forward and understanding what's even deeper below the surface than we've been able to uncover so far. There's much more that we have to learn about. That probably explains some of the remaining cases that are undiagnosed still, and those include some of the genomic changes that you see here, as well as environmental exposures and many other considerations for those unsolved cases. And so our job now is putting together the pieces of the puzzle by looking at the unique patient that we have in front of us, considering the family history, considering the unique genotype of the fetus that we have in front of us any congenital anomalies, the type of abnormal fluid collections, one in pregnancy, these problems presented and then deciding on the most appropriate genetic test. In order to arrive at a diagnosis and focus our care appropriately similar to the field of tulips that you see here of different colors and sizes. There's much more to high drops than simply fluid overload. And we know that so many different genetic diseases can present in the same manner. And so it's essential that we dive deeper in order to understand the true underlying cause and manage the pregnancy and neonatal period. With that specific diagnosis in mind, this precision based approach to care opens the door for personalized approaches to pre and post natal management of disease. Moving forward, for example, we may find that patients with a particular genetic variants are more amenable to one type of intervention in patients with a different genetic variants may be more amenable to a completely different one. This approach to precision based medicine in the prenatal setting will one day completely reshape our approach to management of pregnancies with non immune high drops and other complications. Future goals of our group are to understand the genotype genotype relationship of each of these cases. So understanding, for example, a fetus in front of us with a particular genetic variant, What does that mean about the prognosis for that pregnancy? The prognosis for that fetus and what interventions might be most beneficial for that case. We also want to understand genomic evaluations and dive deeper to investigate additional genomic alterations that may explain non immune high drops. We're also focused on redefining the entire diagnostic approach to non immune high drops and understanding what is the appropriate algorithm to follow for each new case of non immune high drops that presents. We also are very focused on understanding disease specific in utero management strategies, for example, specific surveillance plans during a pregnancy with a specific genetic disease in mind, and ultimately, to understand and apply and develop novel in utero therapies to optimize the outcomes for these fetuses after birth when they might benefit immensely from earlier treatments than is otherwise possible with that, I'll say thank you very much for listening today and I'd be happy to take any questions to the email address that's listed here. A huge thank you to all of our collaborators, as well, as well as our multiple sources of funding that you see listed here.
