CF Screening Test

Question

Hello,
Currently pregnant 2 months and a half, I have a niece who has cystic fibrosis (my sister’s daughter) and my spouse has a cousin, a boy of his mother's sister, who is CF. I wonder if there is a chance we be carriers?

Answer

Hello,
Your sister, mother of a child with cystic fibrosis, is carrier of the mutation she has transmitted to her daughter and that she received from her (your) parents.
The chance that this mutation has also been transmitted to you is 1/2.
For your spouse, the chance he is carrier of the CF mutation of his cousin is 1/4, 1/2 the chance that his mother is a carrier of the same mutation as her sister (the mother of the CF boy) multiplied by 1/2 the risk that your spouse was transmitted the mutation from his mother.
The chance that you and your spouse are both carriers of a CF gene mutation is therefore 1/2 * 1/4 = 1/8. The chance for your couple to transmit your mutation to your offspring is, at each pregnancy, 1/4 * 1/8 = 1/32.
This is a much higher risk than that of a couple who has no family CF history. However, you can specify this risk if you and your spouse perform a genetic test. The calculation of this risk is somewhat complicated to explain.
In case the CF mutations of your relatives have been identified, the risk that two of them have been transmitted to your child, who therefore than has CF is as follows:
- 1/4 if tests reveals that you are carrier of the mutation transmitted by your sister to her CF daughter and your spouse is also carrying the mutation transmitted by his aunt to her CF son;
- Almost zero, if neither you or your spouse are carrying her/his relative’s mutation or if just one of you is a carrier. Almost zero.
In case your CF relative’s mutations have not been identified, a negative test result would not completely eliminate the risk of being carrier because none of the currently available techniques can identify all the CFTR gene mutations (over 2000 known to date). Mass screening kit used in France allows to detect the 30 most common mutations that account for 85% of carriers (and thus missing 15% of carriers); high-speed next generation sequencing techniques, available only in few expert laboratories can identify up to 98% of carriers (and thus missing 2% of carriers).
Therefore, in case of negative test result with the screening kit, the risk of being still carrier of an unidentified CFTR gene mutation can be calculated as follows: 1/34* 15/100 = 1/226 (1/34 being the proportion of CFTR mutation carriers in the French population). The risk of CF would be for your child:
- In case of negative result for one and positive for the other : 1/4 * 1/34 * 15/100 = 1/226 * 1/4 = 1/906, say about 4 times the general population’s risk;
- In case of negative result for you and your spouse: (1/34 * 15/100) * (1/34 * 15/100) * 1/4 = 225 / (4x11 560 000) = 1 / 205 511 say a very weak probability;
In case of negative results with the most efficient sequencing techniques, the risk of being still carrier of an unidentified CFTR gene mutation can be calculated as follows: 1/34 * 2/100 = 1/1 700. The risk for your child to be CF would be :
- In case of negative result for one and positive for the other, of: 1/1.700 * 1/4 = 1/6.800 or less than that of the general population (1/4.700)
- In case of negative result for you and your spouse: 1/1.700 * 1/1.700 * 1/4 = 1/11.560.000 say almost zero.
If you want to get more explanation about the transmission risk calculation, I suggest you contact the CF Center close to your home that will direct you to an expert genetics laboratory which use these most updated techniques. You can access to the map of the French CF Centers by clicking the following link:
www.vaincrelamuco.org/pres-de-chez-vous#tab1

Hope this answer can help.
Best wishes
Gilles RAULT, MD, Roscoff CF Center

25.04.2016