The chance that a person with Stargardt disease and a person without this disease together pass on the condition to their offspring is between 0.7% and 3.1%. This accurate calculation was published by researchers from the Radboudumc in the American Journal of Human Genetics. Thanks to these results, doctors can more accurately inform people with Stargardt disease about the risk of poor vision in their children.
"Imagine that you slowly start to see worse and worse," outlines PhD student Stéphanie Cornelis. "You get the news that this is not going to get better and your vision will continue to deteriorate. The doctor tells you that the form of visual impairment you have, the rare Stargardt disease, is genetic. Therefore, there is a chance that your children will also have this condition. Then an important question is, how likely is it that if you have children, they will also have this disease?"
Until now, there was no good answer to this. A new study by the group of Professor Frans Cremers of the Department of Human Genetics at the Radboudumc in Nijmegen is changing that. The researchers previously published an overview of all the errors in DNA that can cause Stargardt disease. Now they have calculated the risk that offspring will get the disorder, based on data from almost 6000 people with this disease and a control database of the general population.
Two genetic errors
Stargardt disease occurs in one in ten thousand people and is a so-called recessive disease. This means that this type of low vision only develops if the child has inherited an ABCA4 gene with an error from both parents. If someone with Stargardt disease has a child of his own, that child will therefore always receive one of the two faulty genes. The likelihood of the child developing the disease therefore depends largely on any error in the ABCA4 gene coming from the other parent, often a parent without the disease. The question is therefore: how likely is it that someone will carry such a faulty gene without being affected by it themselves?
In the study by Stéphanie Cornelis, Esmee Runhart and colleagues, many of these ABCA4 gene errors were analyzed in detail. Cornelis: "We looked at how often these gene errors occur in the population and investigated what the chance is that a parent without Stargardt disease will nevertheless pass an error in the ABCA4 gene on to their child."
This risk assessment is complex because not all combinations of errors in the ABCA4 gene lead to disease. "Some errors have a more severe effect than others," Cremers explains. "A combination of two mild errors, which are very common in the population, does not lead to disease, while a severe and a mild genetic error together do cause disease." Now it appears that when someone with Stargardt disease and someone without it have a child together, the risk is between 0.7% and 3.1% that the child will also develop Stargardt disease.
Using these results, doctors can more accurately inform people with Stargardt disease about their child's risk of developing low vision. "In addition, the other parent can be genetically tested," Cremers explains. "One can then determine the likelihood of disease even more precisely. But genetic screening is expensive and not available everywhere in the world."
Application to other diseases
According to Cremers, the complex calculation of the chance of disease used in this study can also be applied to other recessive diseases, which only occur when both parents pass on a gene with an error. Cremers: "I think that in the future, this method can very well be used in other diseases, for example Usher syndrome, in which both hearing and vision are affected, or in cystic fibrosis. These diseases also can be due to severe and mild mutations."
This research was published in American Journal of Human Genetics: Personalized Genetic Counseling for Stargardt Disease: Offspring Risk Estimates Based on Variant Severity. Stéphanie S. Cornelis, Esmee H. Runhart, Miriam Bauwens, Zelia Corradi, Elfride de Baere, Susanne Roosing, Lonneke Haer-Wigman, Claire-Marie Dhaenens, Anneke T. Vulto-van Silfhout, Frans P.M. Cremers.
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