Rare diseases are chronic, severe, sometimes life threatening, always costly for the health care and social systems. Prenatal genetic testing and screening are currently proposed to future parents for a number of diseases, and newborn screening is performed after birth in many countries. As technologies become more and more powerful and less expensive, preconception genetic tests of the most frequent mutations of genetic diseases affecting children are now becoming available for use on targeted individuals, or even on the general population.
Prevention of rare diseases is now under discussion: newborn screening in Europe was presented at a meeting of the European Union Committee of Experts on Rare Diseases, and prenatal screening at a meeting of researchers at the Collège de France in Paris. Patient representatives regret that wide variations among countries and regions result in inequalities of access to genetic testing. We believe that individuals and families should be informed about all current possibilities, and supported to make informed choices. But there is still a long way to go!
Newborn screening (NBS) is currently performed on babies in many countries in Europe and all over the world for a very limited number of rare diseases, for which a treatment exists. Though there is absolutely no relation between the number of diseases screened and the GDP per capita : European countries screen very different panels, varying from 2 to 29 diseases. A legal basis for NBS only exists in 17 countries in Europe. Only 9 countries allow parents to dissent or opt out. In 2 countries, the test is never communicated to parents. In 12 countries, parents are only informed at the time when a blood sample is taken from the new born… Speed of analysis is very important, as for some diseases the treatment should start as soon as possible after birth, before a confirmed diagnosis: presently, the timing of blood sampling varies from 1 day after birth to 4 days or more! Quality insurance and quality control procedures, if they exist, focus only on screening tests analysis. All those variations result in very different outcomes for the families.
Information given to the parents about diseases and treatments, training of professionals on how to communicate with families, other stages of laboratory procedures, etc…are not checked neither standardised. An appalling situation.
As an example, In France prenatal screening has been reorganised since 2009 for Down syndrome with a combination of early sonograms (ultrasound scans) and first trimester maternal blood test (which only 80 % of parents accept), followed by amniocentesis if first results show a risk superior to 1 in 250. However only 32% of doctors provide understandable information to parents, 40 % of women say that they did not understand that those tests could end up with the termination of their pregnancy. When the result is negative, many are not aware that they can still deliver a baby affected by many other chromosomal anomalies, or even by Down syndrome, as the current screening strategy will miss some cases.
New blood tests for Down syndrome will soon be available, allowing a quicker and earlier diagnosis, without the 1% abortion risk of an amniocentesis, after 10 weeks of pregnancy. Parents will be asked to take decisions at an earlier stage. Awareness about the issues and informed consent appear more and more like a challenge. Information should be provided before pregnancies. If for cultural, moral and/or religious reasons some mothers decide to keep their babies, they must have access to proper services and support, for their children and for themselves.
Why screen Down syndrome only, and not other rare diseases that are life threatening? Because Down syndrome is a rather frequent disease ? Because it is associated with learning disabilities, as social stigma around « mental deficiencies » is still very strong ? Most people born with Down syndrome today live old, and their quality of life can be quite good if they are adequately supported.
Parents who have a known risk of having children with a severe rare disease, because of family history, can access genetic counselling in general. One may wonder though if it is necessary to have first one affected child in order to qualify for such counseling and preventive option. What is often not known is that the majority of genetic diseases occur as the first case in a family. High speed sequencing of the exome (the coding portion of the genome) or even of the whole genome, is now possible at a decreasing cost. This will help to find long awaited precise genetic diagnosis and propose appropriate counselling for some families. Researchers will soon be able to identify genes responsible for undiagnosed mental deficiencies (currently 50% of them), for the portion of autistic spectrum disorders, or of some other severe psychiatric diseases with early onset, that have a simple genetic cause. But for the general population, taking into consideration that each of us is a carrier of 350 to 400 rare genetic variants of uncertain pathogenic effect, the interpretation of all results is currently an impossible challenge for geneticists: with 3 minutes dedicated to each possible anomaly, a genetic consultation could last more than 15 hours! In the future, geneticists will focus mostly on improving their interpretation of available tests.
The sequencing of 437 genes responsible for severe pediatric diseases on 104 individuals has shown that each of us is a carrier of an average of 2,8 mutations corresponding to the tested recessive diseases, and this could be used soon for preconception testing to identify couples at risk of having children affected with one of these diseases. Preconception genetic tests of the most frequent mutations of 75 genetic diseases affecting children have already been developed. Should a list of genes or diseases be established, to be screened in the general population? What is a severe disease? For example, should it include deafness, whether treatable or not ? What about diseases whose severity cannot be predicted ? Moreover, a disease can be considered severe or not according to the familial and social environment. Phenylketonuria, even detected at birth, is still severe if families do not have access to proper food, that is expensive.
Instead of a list of diseases, should a list of criteria be decided (severity, cost of screening, cost of treatment, etc…)? Can health systems reimburse on a such criteria basis ?
Without public policies impulsed at European level, there is a serious risk that only wealthy and well informed families will access those preconception genetic tests. Should those new tests be evaluated, just like new drugs, by HTA agencies for their efficacy, safety, and compared to existing treatments, before being reimbursed for the whole population?
The issue is extremely complex and needs further work. For preconception screening, offering reproductive options is the main goal. For prenatal screening, informed decision making should be the goal, not prevention. Parents-to-be should never be forced or feel obligated to make a certain choice. In neonatal screening, prevention of disease progression is the goal. Once the diagnosis is made, there is only one choice for the parents: treatment. Offering reproductive options for genetic diseases that cannot be cured is currently under discussion in most countries.
At this stage, three conclusions :
- we need more patient friendly and easily accessible information about risks and life with rare diseases. Parents and Individuals have the right to make informed choices.
- we need to train more geneticists and counsellors in genetics, and encourage more research.
- the use of new technologies should be adapted to people’s needs, not the reverse.
Many thanks to Pr Jean-Louis Mandel, Collège de France, University of Strasbourg, to Pr Luciano Vitozzi, ISS, Italy and their colleagues and teams for sharing their work, bringing researchers and patients together, and triggering those thoughts. Also to Cor Oosterwijk for his support.