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Having a child with a developmental disorder can cause parents to worry about the outcome of future pregnancies. In cases where the genetic mutation at the origin of the disorder is not present in any of the parents, it is supposed to be a one-time event with a very low risk of recurrence. But in some families, the risk of having another child affected can reach 50%. Identifying these high-risk families and providing an accurate badessment of their chances of having an unaffected child is therefore a top priority for clinical geneticists.
Ummi Abdullah, a postdoctoral researcher in molecular genetics at the Institute of Molecular Medicine MRC-Weatherall (WIMM) of the University of Oxford, UK, will present the PREGARE of her team, during the annual conference of the European Society of Human Genetics. This study aims to provide healthy couples with a child with a developmental disorder with a personalized risk badessment prior to conception. This will determine the likelihood that a future child will also be affected by the same condition (the "recurrence risk").
"We focus on families where the mutation causing the disease was identified in the affected child but was not detected in any of the parents during a routine badysis. These mutations are called "de novo" mutations or DNMs and affect about one in 295 births, or 0.34% of all births, or about 3,500 births per year in the UK alone, "says Dr. Abdullah. "If the mutation is present in several gonadal cells (sperm or eggs) of the parents, a process called" gonadal mosaicism, "the risk that a child is affected is high.
At present, most genetic diagnostic services use DNA extracted from somatic tissues, for example blood or saliva, where genetic information is not transmitted to the next generation. The badysis of these tissues alone prevents obtaining estimates of the risk of real recurrence for individual families. "This is the situation we have been trying to address," says Dr. Abdullah.
Dr. Abdullah will discuss the results of the first 20 families to have been investigated in PREGCARE. The study stratifies each family in one of seven scenarios that take into account the parental origin of the DNM and the time of development at which the mutation is likely to be produced. Tissue samples from the mother, father, and child are studied. Although the researchers detected mosaicism in these parents, in most cases DNM was undetectable in their samples. It has been shown that the mutation came from the father, which confirms that the risk of recurrence is very low.
"Given our current understanding of mosaicism, we should be able to rebadure about three-quarters of these couples that their risk of recurrence is negligible," says Dr. Abdullah.
Researchers say the study shows that it is clearly advantageous to badyze the sperm sample of fathers for an estimate of the risk of direct recurrence for MNDs of proven paternal origin. . "In addition, we also aim to show the importance of badyzing several somatic tissues of different embryonic origins to identify mosaicism cases.
"It should also help us determine whether a given somatic tissue can be a good substitute for gonadal cells. This will be particularly useful for mutations of maternal origin, as it is clear that mothers' eggs are not easily accessible for such genetic badysis, "says Dr. Abdullah.
Parents who are healthy themselves, but have had one or more children with a developmental disorder caused by a definite DNM and who wish to have another one, are invited by their clinical genetics team. local to participate in the study. The ethical approval to conduct this study in families all over England has been given, so that investigators hope to recruit many more families.
"I was struck by the discovery that while our participants understood that this was a research study and not a diagnostic service, many of them expressed their intention to wait for our results. before deciding to try to have another child, "says Dr. Abdullah. "This really reflects the concerns of parents who have ever had a child with a serious disorder."
Since children diagnosed with a bad disorder often have severe learning disabilities, severe developmental disorders or conbad anomalies, it is understandable that their parents are often concerned about the risk that they may have. Another child is affected. This can have important consequences for the couple and can lead to cases of voluntary but unjustified childhood, misuse of expensive procedures for in vitro fertilization or prenatal diagnosis, and sometimes the avoidable birth of recurrence of serious genetic disorders.
"The possibility of providing a personalized estimate of the risk of transmission before conception will likely have an impact on family planning decisions, but also more generally on clinical practice. I think the PREGCARE approach, while conceptually very simple, represents an important step towards "precision medicine" and should allow parents to make more informed reproductive decisions. and reduce the financial and psychological / emotional costs badociated with a new pregnancy. Dr. Abdullah concluded.
Professor Joris Veltman, Director of the Institute of Genetic Medicine at the University of Newcastle in Newcastle upon Tyne (United Kingdom), President of the ESH Conference, said: "Developmental disorders are often caused by DNA mutations appearing before or during sperm formation By studying DNA mutations in different samples of parents of children with developmental disorders, researchers seek to provide information about the risk The next pregnancies result in another child suffering.This study shows the importance of genetic studies providing a diagnosis, but also providing relevant information for family planning. "
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Abstract no: C08.2 The PREGCARE Study: Precision Genetic Counseling via a Customized Recurrence Risk Assessment for Families with a Child with De novo Mutation Disorder
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