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Disease and treatment

Prenatal exome sequencing: doctors’ experiences

Doctors in Denmark have been able to carry out prenatal whole-exome sequencing for 2 years, and the researchers are now sharing their experiences.

The worst nightmare of all expectant parents is being told that there may be something wrong with their unborn child.

So far, it has even been difficult for doctors to provide anything but guesses as to what causes prenatal malformations detected by prenatal scanning. Doctors could only diagnose a few congenital disorders.

However, everything has changed within the past few years as a result of technological advances that have enabled doctors to use whole-genome or whole-exome analyses on invasive samples (either amniocentesis or chorionic villus sampling from the placenta) to test for genetic disorders. The exome is the part of the genome that generates proteins and therefore reveals much of the available genomic information about potential genetic disorders.

These whole-exome analyses provide unique opportunities to prepare parents for their possible future in the short and long term. However, sometimes this also poses ethical dilemmas for doctors.

“The benefits of this new technology will radically improve the opportunities for diagnosing severe disorders in fetuses and unborn children. But like all technological advances, we need to know both the benefits and the disadvantages of the technology,” explains Ida Vogel, Clinical Professor, Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital.

Ida Vogel and colleagues have published an article in Acta Obstetricia et Gynecologica Scandinavica on their experiences of using whole-exome sequencing in pregnancy.

Greatly increases doctors’ opportunities to diagnose genetic disorders

In Denmark, all pregnant women are routinely offered prenatal scanning at a hospital to confirm that their unborn child is doing well, developing as it should and does not immediately show any evidence of a genetic disorder such as Down’s syndrome.

For most women, undergoing prenatal scanning to confirm that all is well is routine.

However, early nuchal translucency scanning cannot typically be used to diagnose anything other than Down’s syndrome. Doctors have therefore had very limited opportunities to tell expectant parents whether there is anything else wrong with their unborn child.

Whole-genome and whole-exome sequencing has been a game-changer, and if doctors, molecular biologists and bioanalysts discover malformations in prenatal scanning, they can use amniocentesis or chorionic villus sampling to examine the genes for numerous genetic disorders.

Some disorders can be serious and fatal, and others may cause learning disabilities or possibly autism later in life.

Enables prenatal diagnoses never previously possible

Over the past 2 years, doctors at Aarhus University Hospital have carried out whole-exome sequencing on 35 fetuses, and data from the studies show that doctors have a very potent diagnostic tool at their disposal.

The data show that doctors could make an accurate diagnosis in 25% of cases that could not have been made just a few years ago.

The doctors from Aarhus University Hospital, for example, have made several prenatal diagnoses that have never previously been made anywhere else in the world.

Two sets of parents were each told that their unborn children had a life-threatening congenital disorder of glycosylation, and both children died immediately after birth.

“Technology enables us to prepare future parents for what may happen. Then we can be ready and, for example, plan optimal treatment by having specialist paediatricians present during delivery. A child may also need to be born in a specialist treatment centre, or if the prognosis is very unfavourable, the parents can prepare themselves for this before the child is born. It may be important to be able to go for a walk with the baby in the stroller just once or baptize the baby immediately. In any case, it is important for parents to be with their newborn child in a peaceful environment for the few days they can be together,” explains Ida Vogel.

Ida Vogel also says that these genetic tests will put doctors in a much better position when considering future pharmaceutical and other forms of treatment if they already know what the unborn child needs before the birth.

“If the method is used on an already born child who is ill, the diagnosis usually does not change much. However, everything changes if we can make the diagnosis early in pregnancy. In some cases, the parents may decide that they do not want the child because they are too daunted by the prognosis of the disorder, but in other cases we can prepare as optimally as possible for the birth,” says Ida Vogel.

Testing can eliminate concerns about several horrific diseases

Experience with whole-genome and whole-exome sequencing during pregnancy also shows that it can provide positive answers.

In many cases, doctors at Aarhus University Hospital have been able to eliminate concerns about many serious diseases caused by anomalies found in prenatal scanning.

“There are some disorders we do not know anything about and cannot exclude through whole-exome sequencing, but it is really great to be able to eliminate concerns about the disorders we do know something about. Previously, when prenatal prenatal scanning revealed a congenital heart defect, we could not say whether the child had only this heart defect or whether the heart defect could be part of a genetic disorder. We can answer that question much more accurately now. If the changes are not found in the genes, the risk of having a child with multiple disabilities declines significantly,” says Ida Vogel.

Sharing experiences is important

Ida Vogel explains that everyone should share their experiences with this new technology so that doctors and patients can learn from each other.

“Every time we change the diagnostic options, we end up in uncharted territory and cannot rely on anything we have done in the past. We must then map our own experiences and share them,” says Ida Vogel.

At Aarhus University, whole-genome or whole-exome sequencing is an everyday routine, and Ida Vogel wants to increase the number of monthly examinations to between 10 and 20, so that all women whose prenatal scanning shows a severe malformation are offered genetic screening.

“We just need to get started and learn as much as possible about the pros and cons of using this technology. The benefits are obvious, but we also face some problems we have not encountered before. The answers provided by genetics are not simply black and white. Sometimes the answers are grey, and we need to be ready to tell parents, for example, that their children may be at increased risk of developing a learning difficulties but that we cannot be sure. When the effects of our communication are so great, any misinterpretation of data will also have a much greater impact, and here, together with parents, we must learn how to best provide grey answers. It is also important to teach the pregnant women and their partners that they can decide for themselves how much they want to be told,” says Ida Vogel.

The journal article below discusses the ethical issues associated with prenatal whole-genome or whole-exome sequencing in greater detail.

Implementation of exome sequencing in fetal diagnostics – data and experiences from a tertiary center in Denmark” has been published in Acta Obstetricia et Gynecologica Scandinavica. In 2016, the Novo Nordisk Foundation awarded a grant to Ida Vogel for the project Prenatal Testing in Denmark – Detection, Counselling and Outcome.

Ida Vogel
Clinical Professor
Ida Vogel and her colleagues ensure that the examination and treatment of pregnant women is based on the newest diagnostic methods; both in connection with the screening of all pregnant women and for diagnosis in cases where the foetus shows signs of congenital anomalies. Early diagnosis is also a help for medical doctors, enabling them to provide the best possible treatment in connection with birth and infancy, while also giving pregnant women the opportunity to take any precautionary measures early in the pregnancy if the foetus has e.g. a genetic defect.