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Carriers screening

Question
Dear Expert,

In carriers screening, what is the preferred/recommended action when one of the parents has a known mutation that causes CF, and the other parent is negative to the standard 10 CF mutations panel (of his country). Please note, the mutation spectrum of the ethnic origin of the second parent is not well defined (there are no CF mutations that characterize his ethnic origin).

Thank you and best regards,
Answer
Dear questioner

The only way to get CF is to have two genes that cause CF. This means that both parents individually must be carriers of a CF mutation. When both parents carry the CF gene, there is a 25% chance that their child will have CF. The risk of carrying a CF mutation depends on ethnic origin. For Caucasians the risk is approximately 1 in 20. On the other hand, the risk for Asian-Americans is of the order of 1 in 90.

In this case, the fact that one parent has no identified mutations on a standard CF panel is very reassuring, and the chances of their children having CF is statistically very low indeed. The risk however is not zero. New mutations are continually being identified, and panels akin to this only check for the more common mutations. Furthermore, higher classes of mutations are less likely to be screened for which often confer milder disease. So the likelihood of a couple with one carrier and the other partner tested negative of having a child with CF depends on the detection rate of the underlying genetic test. Normally, commercial assays include around 30-40 CF-causing mutations and achieve mutations detection rates ranging from minimally (70%) to optimally (90%) depending on the distribution of mutations in a certain population. Mathematical models calculate the risk of a "one positive/one negative" couple having a child with CF to be around 1/400 (when test-sensitivity is 70%) and to be around 1/1200 when test sensitivity is increased to 90%.

So to further reduce the possibility of having a child with CF in a case like yours it is recommendable to do genetic testing in the negative partner with a more sensitive CFTR mutations panel, if possible tailored to the ethnic origin of the negative partner. Otherwise one should be aware of the fact that people from ethnic groups that have a lower sensitivity for detection than the majority for how the screening panel was selected, have a higher risk of an underlying undetected mutation.

Regards

Dr David Comer and Dr. D. d'Alquen
03.07.2012