Welcome Ambry Genetics

[StevenKeiles]

Felicia.

Excellent question and I am not sure it is really well understood. There are also other genes that interact with CFTR and can modify the effect on the protein. some can be a positive influence and some can be negative. It is these modifier genes that probably contribute a lot to the variability of symptoms within mutations as well as within families.

Steve

 

[StevenKeiles]

missT

The 5T is like a mild to moderate mutation. when paired with R117H it acts like a moderate or severe mutation. I am guessing the two are in cis on the opposite chromosome from the W1282X since that is usually on a 7T chromosome. I would expect this combination to result in moderate to severe disease depending on how many TG repeats are also linked with the 5T, when you have 12 or 13 you have more severe symptoms, and with 11 repeats is not as bad.

Hope that helps.

steve

 

[cerdaclan]

Hello,

I am a VERY confused mom of two daughters, 9 and 7. They have moderate bronchiectesis, chronic pan sinusitus, etc. They are 1/2 hispanic. Both have had 3 consecutive sweat chloride tests that were borderline at 39 and 49. The tests, repeated 3 times in the same lab had exactly the same reading each time. They were tested at a different lab once where it took them 2 hours to collect enough sweat and the technician moved the pads to several locations during the tests to try to get the sweat to the desired line. This particular test resulted in a reading of 29 in both. We were told that sweat tests were the gold standard. They went on to perform the ambry test including the deletion and this came back negative in both children. We are now in a quandry. My children are being treated as though the have CF. They are on dornase alpha, the hilrom vest, nubulized saline and are also on immunoglobin. They also have specific antibody disorder. This past week, both had additional blood test results that came back showing elevation of serum B12 and folate. They have a horrible time with mucous and neither can attend school because each time they are exposed to a cold, they get pneumonia, sometimes as many as 8 times a year. Their pulmonologist is relying 100 percent on the ambry test and is certain they do not have CF, but continues to treat them with them with a CF protocol. They saw a geneticist last year that felt they were falling through the cracks for a dx of CF and was certain they had it. We are so confused. My questions are:

How accurate is the Ambry testing in diagnosing? Can it miss? I read that it is only 78 percent accurate in hispanic children.

It was recommended by the geneticists that they have an NPD done as it is nearly impossible to get enough sweat from my daugther that is most symptommatic. If we have this done and it comes back positive, will they still dismiss it because ambry was negative.

On one hand, is seems that they say the sweat test is the gold standard, but then argue that if ambry is negative, they do not have it. In the meantime, my daughters are getting sicker and sicker, with growing mucous clearance issues, despite all the meds.

I would love to hear what the ambry person has to say?

 

[StevenKeiles]

Cerdaclan,

The ambry Test can detect 99% of all mutations, so it is possible to have CF and not find mutations however it is unlikely. The important thing to remember is that this diagnosis which can be difficult in atypical cases is not based only on one thing. It is a combination of clinical presentation, sweat test, genetics and other test results as well. It is really the doctor who makes the diagnosis using all of these tools. When they all say CF it is easy, but when there is conflicting or ambiguous results it can be very difficult. I know that doesn't really answer the question, but I hope you understand the complexity especially for some cases.

Best of luck,

Steve

 

[k8sbigfan]

Hi, Steve. Thank you so much for answering everyone's questions. I am learning alot from this site and others.
I am not sure that I understand what some things mean.

My daughter is deltaF508 (from my husband) on exon 10 of the CFTR gene. I have given her the mutation 4218insT on exon22 of the CFTR gene. The report states that the "single base pair insertion results in a frameshift mutation in exon 22 of the CFTR gene". Kate also carries the 7T/9T poly T variant.

I have been trying to find info about how a frameshift mutation may make CF more serious....does this depend on the certain mutation or combination of mutations? Also, I can't find very much about the 7T/9T poly variant effect on the possible severity of the CF disease.

Any info/help would be appreciated, or if you could refer me to any sites/journals/etc. I have been on the genome website to gain info.

Thanks,
Kay

 

[brandismith36]

Hi,

I was just diagnosed with CF and I am 36. Can you give me information on the R117H/3905insT compound 5T/7T. Any information is greatly appreciated.

Thanks,
brandismith36

 

[annonymous]

Hi Steve,

We had the full Ambry done in 2006 and my child was identified as a carrier of Delta F508. No other mutation was found. I would like to know how often you discover new mutations because we are trying to figure out when we should do the test again. Would it be worth doing now, or should we wait longer until more are found? And if it is worth doing now, will you only test for the new mutations without having to do the whole test again? I am assuming it would be less expensive if you could test for only those mutations that weren't in the panel the first time.

My child had one positive newborn screening and one negative newborn screening. He has had positive and borderline sweat tests. All other tests (stool, vitamins, x-rays, etc.) are normal. He has had no out of the ordinary symptoms of CF, other than I think he is a little salty around his hairline on hot days (hence the elevated sweat tests). I've read that there are some people that have negative sweat tests, but in fact do have CF. I guess I continue to hold out hope that maybe some people can have elevated sweat tests and NOT have CF.

Thank You.
MT

 

[StevenKeiles]

Kay,

Usually frameshift mutations are more moderate to severe mutations, but there are always exceptions and even severe mutations are not severe all the time. So unfortunately, there is no exact way to predict with any mutation.

The poly T variant is usually a 7 or 9 so those are normal.
I hope that helps.

Steve

 

[StevenKeiles]

Brandi,

If the R117H is with the 5T, it makes it more severe especially if there are 12 or more TG repeats with the 5T. The other mutation is a more typically mutation and the combination could cause anywhere from mild to moderate CF. I would not expect a classic presentation with this combination so being diagnosed at age 36 fits the findings.

Best of luck to you.

Steve

 

[StevenKeiles]

MT,

Things have not changed very much at all with our testing since 2006, but there are a couple of things we do now that may not have been done in 2006. I would need to check on your results to let you know.

Reply to my ambry email with your child's name and birthdate so I can check and respond to you privately.

thanks,

Steve

 

[Lety]

Hi Steve

My daughter was diagnosed with DDF508 back in april 2008. Last week we sent my son's (from a previous marriage) kit. Can you please let me know if you got the kit and when can we get the results. We need to know if he is a carrier of F508 First. My son is going back to South America soon. He would like to take the results with him.

His name is Alan Marinkovic and he is 21 years old.

Thanks so much.

 

[StevenKeiles]

Lety,
Yes we did recieve the sample and it is being processed now. Results should take approximately another 2 weeks.

Steve

 

[Lety]

Steve

What are the chances (%) of my son of being a carrier of DF508. He is from a previous marriage. I'm a DF508 carrier mom to daughter with CF. Thanks

 

[StevenKeiles]

Lety,

It would be at least 50% chance.

Steve

 

[MLR041607]

Dear Steve,

Thank you in advance for any information you are able to give me.

I am a carrier of the 5'UTR-680T>G mutation. My husband is a carrier of the p.L1335F mutation and c.1812-1_-2insA novel variant (both on the same chromosome). We have one son who is a carrier (inherrited my mutation). We did not know that we were carriers before having our son. We now know that we have a 25% chance of having a CF child with each pregnancy. We are weighing our options about expanding our family and I was wondering if you could give me some information on our mutations and possibly the combination of our mutations together. I realize that this is probably a very complicated question, but any information would be helpful

Thanks again,

 

[mama9909]

Hi Steve, I have a few questions for you...my son was born this past October. At 4 weeks old he was admitted into our local Childrens hospital for failure to thrive, his weight at that point was only 5lbs 8oz, still below his birth weight of 6lbs. I had talked to our primary several times about his BM's not being "normal". In the hospital they did a fecal elastase which was 160, sweat test was normal at 18. They put him on a 26 calorie diet to help him gain weight, which worked..he was able to catch up. We finally got into the CF clinic about a month ago. They repeated his facal elastase which was 360 this time, repeat sweat test was 7.5. He was put on enzymes and taken off the high calorie diet and stopped gaining weight again. Since being on the enzymes he eats less frequently, he was eating every 2 1/2 hours before and now only every 4 hours, his BM's are less frequest, only twice a day now, but still diarrhea and still very stinky, he has less gas and he is less fussy and able to sleep better now. But the GI doc is planning to take him off the enzymes if the bloodwork comes back with nothing found. He has had bronchilitis once already, and has had chronic diarrhea since he was born, also has reflux. He is always fussy and was told by our primary that it is "just cholic". He has had low grade fevers of unknown origin, and also has hydronephrosis of his kidney. I do not know if that could at all be related to CF. Currently we are waiting for the bloodwork to come back testing him for CF. I have no idea where it was sent to. It has been two weeks since the bloodwork was done and I still havent heard anything. I have a nephew that was tested for CF, I have no idea what type of test was done but it didnt find anything, also my sons step-brother was suspected of having CF. Unfortunently I have had no contact with his father so I do not know the outcome of his situation. I guess what I am looking for is a little advice. If no mutations are found does he in no way have CF. With his symptoms should I push for further testing? Can he be Dx with CF based on these symptoms? His father is hispanic, do hispanics normally have mutations that are more rare? Any advice you could give me would be greatly appreciated. Im still just trying to understand all of this and get some answers from our doctors.

 

[StevenKeiles]

Mama,

If the sweats are that normal and the CF sequence does not show any mutations, I would think it is highly unlikely to be CF related. Not exactly sure what the next steps would be but I think a sweat of less than 15 and a normal sequence in my opinion basically rule out CF.

Steve

 

[StevenKeiles]

Michelle,

I would guess that your husbands mutation is more like a typical CF causing mutation. However, it is likely that your mutation is more of a mild to moderate mutation. It does appear to be something we see many times but often not with another mutation. We do have some patients with symptoms that have this variant but most of the patients only have this one variant which makes me think this is a mild to moderate mutation at worst and may not cause symptoms in a lot of people even if they do have another variant. We just can't be certain at this time.

Sorry I could not be more helpful.

Steve

 

[caraweger]

Steve, I had spoken with you almost a year ago about my daughter's mutations. I live in Canada. The first panal found NO mutation, then it was sent on to the Toronto lab where they ran the full panal. They found one mutation be rare...303G<A (Trp57X), and the other mutation was a deletion on exon 23 and 24. When I had spoken with you before you had said I had to be mistake about the deletion. But we did run two additional tests to be sure. And that is what they are finding. Mutation not in the database, so new mutation. My husband and myself were then tested to see who carried what mutation. I am a carrier of (Trp57X), but after doing two genetic tests on my husband he was found not be a carrier in the traditional sense. After meeting with the geneticist she gave us two potential explanations. My husband could be a germline mosaic...to the best of her knowledge this has never been seen before in CF, but is possible, or this mutation could have happened for the first time in my daugther (one of his sperm mutated), new mutations have to start somewhere. Just wondered what your thoughts and/or knowledge was in this circumstance, and what you can tell me about those two mutations.

Thank you Steve.

 

[caraweger]

Steve, not sure why the whole msg did not come through? Mutations found were 303G<A (Trp57X), and deletions on exons 23, 24. We were told that Mutation (Trp57X) was relatively rare, and the deletion mutation was not in the database at all. When we had spoke before you had thought I was mistaken about the deletion, but we have done three tests to confirm, and I am looking at the paper from the geneticist. My husband and I have both been tested, I am a carrier of (Trp57X) but my husband is not a carrier in the traditional sense. The explanation that was given, is that it is possible, that he is a germline mosaic, or that this has happened for the first time in Teresa (once of my husbands sperm mutated), new mutations need to start somewhere. Just wondering your thoughts and/or knowledge on this. As well, if you knew what class the (Trp57X) falls in to...is this a stop mutation? Thanks for your help Steve.