BabyFox project explores accelerating whole genome sequencing

In September this year, the BabyFox project was launched within the Precision Medicine Centre. Its primary goal is to obtain rapid whole-genome sequencing (rWGS) results for patients with genetic diseases in neonatal and pediatric intensive care units in the shortest possible time, or within seven days. Similar projects are already underway in other countries, such as BabyLion in Germany, BabyBambi in Israel and BabyBear in California. The research team is led by Prof. RNDr. Ondřej Slabý, Ph.D., who describes the BabyFox project in our interview.

Which institutions supported this project and for how long?

The coordinating institution of the BabyFox study is the Centre for Precision Medicine and the Paediatric Clinic of the Brno University Hospital. The final approval of patient inclusion in the study (MUDr. Kateřina Slabá), rapid whole-genome sequencing, interpretation of findings and preparation of protocols (Mgr. Petra Pokorná) are also carried out here. Co-principal investigator of the project is prof. MUDr. Milan Macek, DrSc. (FN Motol Centre, Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and FN Motol). After the project was approved, Prof. Tomáš Honzík, M.D., Ph.D. (VFN Prague, Department of Paediatrics and Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague) joined the project. A large number of colleagues are involved in the project at our and our co-researchers' departments, but it is not possible to name them all here. We have managed to secure funding for the BabyFox project from Illumina, and it should last for the next 18 months. It is planned to include 60 patients and their parents. In total, 180 genomes will be sequenced.

Is it genome-wide sequencing (rWGS) of seriously ill newborns and children? What is or can be the diagnosis?

Yes, it is so-called rapid whole genome sequencing, which means that the resultant whole genome sequencing protocol must be issued within seven days of the collection of the biological material, i.e. the blood collection of the patient and his/her parents. The cost of such a test per patient and parent is approximately 250 000 EUR. CZK. After the first month of the study, we have already enrolled five patients. In all of them, a results report was issued within seven days of collection, in four cases even within five days, and in two of them a diagnosis was made. In terms of feasibility, it seems that we should not have encountered any major obstacles so far. Unlike most other "Baby Projects" that were designed exclusively for newborns, our study is not only for newborns but also for older children admitted to intensive care units. For example, the continuation of the Israeli BabyBambi 2 project already covers the paediatric population as well. However, for paediatric patients, there is less clinical evidence yet on the clinical applicability of this approach. As far as the entry criteria for inclusion in the study are concerned, they are quite broad. It includes any neonate or child admitted to an intensive care unit with a suspected monogenic genetic disease. So if you are asking what the diagnosis might be, the answer is that it must be an unknown diagnosis at the time of inclusion in the study.

Apart from diagnosis, can rWGS have other clinical implications for neonatal and pediatric patients?

Genetic diseases, and especially rare genetic disorders, are a significant factor in mortality in the neonatal and pediatric ICU. The whole project is being implemented precisely because rapid genetic diagnosis has important clinical implications. The diagnostic yield, i.e. the establishment of a causal diagnosis, is around 40% of cases according to the studies published so far, and in these patients up to 80% of cases the establishment of a diagnosis had an impact on follow-up care. The clinical utility of this test, i.e. the impact on follow-up care, is divided in the project into five main categories: change of medication, surgery, palliative care, clinical research opportunity or dietary measures, and then according to the standardised C-Guide (Clinician-reported Genetic Testing Utility InDEx).

The project envisages rapid sequencing to speed up the results. Will it take into account the child's parents, etc.?

Of course it will. The major qualitative change compared to standard genetic diagnostics is the time factor, and also the complexity of the examination. Our reimbursement system only reaches the so-called whole-exome sequencing (coding a part of the genome, about 2% of its total sequence) for a defined group of patients, and its execution and evaluation is normally calculated in a few months. However, this may already be too late, especially in the case of severely ill newborns. In addition, whole-genome testing increases the diagnostic yield compared to whole-exome testing, which is further increased by the so-called trio setup, where we sequence the genomes of both parents at the same time as the child's genome, which is crucial for the interpretation of the findings.

What specialisations does this project cover?

The key specialties for this project are primarily paediatricians and neonatologists who identify suitable candidates for the study, describe their phenotype in detail and ultimately enrol the baby or neonate in the study. In addition, molecular biologists and geneticists perform whole genome sequencing and interpret the findings. And then the attending physicians, who will take these findings into account in follow-up care as soon as possible, if the possibility exists. In the case of positive findings and confirmation of genetic disease, medical geneticists are also called in to provide genetic counselling for the whole family, but this may take place over a longer period of time.

What number of newborns are we talking about?

As far as newborns are concerned, it will be in the low tens of cases per year for the whole country. In the paediatric population, the number of patients potentially enrolled in the BabyFox study is significantly higher. Often these may be chronically ill patients without a diagnosis, who are on their diagnostic odysseys, and who may return repeatedly to the ICU due to deterioration in their health, and even years after the first symptoms have manifested, still have not received their diagnosis. We cannot estimate how many such patients are currently in the Czech health system. Last year, the first specialised outpatient clinic in the Czech Republic was opened for these patients at the Paediatric Clinic of the Brno University Hospital. In cooperation with the CREATIC centre, we are establishing a clinical registry for them, and we are implementing a number of other follow-up activities. But that's a whole other story. More information about these activities can be found on the website of the Centre for Precision Medicine of the Brno University Hospital (www.fnbrno.cz/cpm/).

How can the results of the study be translated into the actual care of such young patients?

Knowledge of the diagnosis can be translated into follow-up care in the ways we classify clinical utility, i.e. by changing medication, performing or cancelling surgery, allowing inclusion in a clinical trial, dietary measures. Unfortunately, the transition to palliative care is also an option. For example, neonatal encephalopathies (brain damage), which often have similar symptoms, can be caused by up to 1500 different genetic diseases. Making a correct genetic diagnosis quickly is absolutely crucial, due to the risk of permanent neurological damage or death. For example, one cause may be thiamine metabolism dysfunction syndrome type 2 (THMD2), a rare genetic disorder related to thiamine transport in neurons. If the diagnosis is made early in newborns, treatment with thiamine and biotin, a common B vitamin, can be started immediately. If treatment is started quickly enough, babies can be completely unaffected. Otherwise, the course of the disease is usually fatal in infancy or early childhood.

Why did you choose the name BabyFox?

As the coordinator of the study, I was able to choose the animal for the Czech study. In the end it was our daughter Veronika who chose the fox, so we have BabyFox in the Czech Republic.

Press release FN Brno