Risk for cystic fibrosis: carrier father, no carrier mother (??)

Question

Hello,
I am contacting you because I am pregnant in the 3rd month now and I have concerns about my baby and a possible disease.
We have learned recently that my husband's niece (daughter of his sister) was diagnosed with cystic fibrosis. We inquired about the disease and its transmission and had blood tests with a geneticist.
She asked us about our origins and family history: My husband has a Norman family and his niece is the only CF person in his family. I am from Vendée and I have no cases of CF in my family.
We also learned that the niece of my husband is a carrier of two rare mutations (Y1092X and S945L).
Blood tests revealed that neither my husband nor I were carriers of one of the 32 mutations of the testing kit.
Until today we were expecting the result for the rare familial mutation for my husband.
We talked and had understood that the antenatal diagnosis would not reveal if our child was sick or not, but if it was carrying the mutation from his father or not. Do we have it right?
Today we learned that my husband carries the rare familial mutation (I do not know where it is). We are in shock. But from what we understand, the risk of having a sick child still thin ...
Despite myself I need to quantify this risk.
Dialogue is difficult with the geneticist who takes care of our record. I need clear answers. I also need kindness and a minimum of empathy. In his presence I do not feel it and that's why I'm posting here my questions.
Can you help me quantify the risk that my child is sick? And what is the risk that I be a carrier of a rare mutation? (If I understand, being from Vendée, I have more risks than an other person?)
I also wanted to know how to diagnose this disease after birth. I did some research and read that there was a sweat test. But I do not know much and I would really like to know if these tests are made on the day of birth or whether to wait a few days? And in which time the results are given ...?
The antenatal diagnosis was not any more on the agenda (not giving us unconfident about the disease response), but now with the shock of the announcement, I put this decision into question. And what if the echo in the 5th month shows alarming signs? Would it not be wise to have also diagnosed the unborn to have answers the most accurate as possible?
That's where I am with my questioning. Thank you in advance for all the help you can give me.

Answer

Hello,
You ask for the calculation of the risk for you as a couple to give birth to a child with cystic fibrosis.
Cystic fibrosis is a recessive disease, couples at risk of transmitting cystic fibrosis (CF) are those whose two members are carriers of a mutation in the CFTR gene (there are nearly 2,000 currently known mutations of this gene). As can be shown in a family tree, with each pregnancy, these couples have a statistical risk:
- 1 in 4, transmit 2 mutations (1 from the mother and 1 from the father) and thus give birth to a child with cystic fibrosis;
- 1 in 4, give birth to a child neither sick of CF nor carrier of one CFTR gene mutation;
- 1 in 2, to give birth to a child with one CFTR gene mutation (1/4 from the father and 1/4 from the mother), so no sick child but carrier of one mutation that could possibly pass on to its offspring.
For couples who have no known family history of CF, the risk can be derived from the prevalence (frequency) of people carrying a CFTR gene mutation. This prevalence may itself be deduced from that of CF at birth. It has been known since the generalization of systematic CF newborn screening: at present, it is close to 1 in 4624 births, couples at risk of transmitting the disease is 1/4 for each pregnancy, they deduced number is 1156 (4624/4) and the deduced frequency of the CFTR mutation carriers: 1/34 (1 / square root of 1156).
In cases where one member of a couple has a family history of CF, the risk for this couple to transmit the disease increases and depends on the degree of relationship with the patient. In your case, the family history is the niece of your husband. A mutation of this niece was therefore transmitted from her mother (your husband's sister) by a parent (grandparents of the niece). The probability that this maternal grandparent has transmitted this mutation to your husband is 1/2. It was therefore important to look for the presence of these two mutations in your husband. Molecular genetic blood test concluded that he carries none of the 32 most common mutations but carries one of two rare mutations found in his niece. The probability that he forwarded it to your child is actually ½.
You actually have well understood what the geneticist told you. He applied the recommendations of the French Society of Genetics: they are, for the spouse of a holder of a single CFTR gene mutation, to search for the 32 main mutations of the French population (excluding specific geographical origin evoking the frequency of a mutation out of kit (it is not your case). This kit can detect 85% of carriers of a CFTR gene mutation. This research was negative for you, the probability that you are carrying another CFTR mutation goes from 1/34 to 1/34 * 15/100 is 1/227.
Following the tests, the risk that your child is CF is ½ * 1/34 * 15/100 * 1/2 = 1/890 which is the product of i) the risk of transmission of the mutation of your spouse (1/2) ii) the risk that you are carrying an out of kit mutation (1/34 * 15/100) iii) the risk of transmission of this mutation (1/2). This non-zero but low risk does not justify the risk of miscarriage caused by amniocentesis for prenatal diagnosis (it is estimated between 0.5 to 1%).
It should be noted that mutation detection techniques have greatly improved since that recommendations for cystic fibrosis have been published. The new generation sequencing technique (NGS) detects 98% of carriers instead of 85% of the 32 main mutations kit. This technique is mastered by several molecular genetics laboratories in France including 3 Reference Centres of the GenMucoFrance network (Cochin Paris, Montpellier and Brest). Negative, the result of this technique would perpetuate a risk of 1/34 * 2/100, is 1/1700. Positive identification of two mutations carried by the parents would lead to a prenatal diagnosis which, if positive, would raise the question of a possible pregnancy termination.
To answer to your last question, the sweat test can be performed a few weeks after birth when the baby weights 3 kg or more.
Hope these details will help and will moderate your concern.
With my best wishes for the New Year and long and happy life for the child you carry.
Sincerely.
Gilles RAULT, MD, Roscoff CF Center

13.03.2015