Welcome Ambry Genetics


New member
Steven (Ambry)

hi steve,
Im going to call my sons gastro dr. at chop on monday to see if we
can run the deletion test. also to see if we can do the nasal
testing for pollups that would give more of an answer. my son
malabsorbs and goes to the bathroom at least 3 or 4 times a day,
and has stomache aches every time he eats. do you think enzymes
would help the aches and help him gain weight has gained nothing in
a year and a half? thanks for your time.
mother4 (jane)


New member
Steven (Ambry)

<span style=" color: #0000ff; font-size: medium;">Question for the
Ambry guy:</span><span style=" font-size: medium;">
My son Joshua is 12, and was diagnosed officially by nasal
differential potential testing on 09/17/06. His sweat chloride at
Hopkins was a 15; he was also positive for CF on a different
type of sweat chloride test that stimulates sweat from a alternate
channel. We had his first clinic appointment on Tuesday and the
doctor said she called the lab (Quest) and they were almost
finished his mutation panel. They found no mutation match and only
had one more group to go through (I think she said of 27 groups).
The basic mutation screen was done at Hopkins. She said there is a
very small number of families across the US that test
positive for CF, have symptoms, but show no genetic mutation.
Further they suspect that a gene that has yet to be identified is
most likely involved. Any thoughts?</span>
<span style=" font-size: medium;">His primary symptoms are asthma
and sinus infections, and some bronchitis. Had sinus surgery
in May that revealed polyps.</span> <strong>


New member
Steven (Ambry)


We have seen that mutation a handful of time in affected people. Not a lot of specfic information, but it does appear to be a typical CF causing mutation.


Your son's GI doc would be the best person to assess the usefulness of enzymes. You can discuss that as well at your next visit.


It sounds like if Quest is checking 27 groups, they are probably sequencing the gene and not just looking at a panel. If he is negative for mutations, that would not surprise me with a sweat of 15. I would probably agree about another gene than can cause some of the same symptoms seen as in CF but with negative sweat tests and negative genetics. Maybe some time in the near future we will have some more of the answers.



New member
Genetics testing

I was recently diagnosed at the age of 25 as having cystic fibrosis. This diagnosis was based on three definitely positive sweat tests. After seeing the cf clinic for a while, they sent my bloodwork off for analysis at Ambry through the full mutation analysis. I'm not sure if it had the deletion, but I know it was all the mutations.

Well, not a single mutation was found, much less two. When I first heard this, my thought was well, I guess this means the diagnosis was incorrect. However, the doctor at the CF clinic said that the mutation panel meant nothing. He said based on my sweat tests combined with the appearance of my sinuses in sinus CT scans, what my mucus looks like (apparently CF mucus even healthy looks different if you're experienced), testing as pancreatic insufficient (though I'd survived 25 years without enzymes - life is better with them) and other factors, he feels absolutely confident that I have cystic fibrosis.

First, does this make any sense at all? If you sequenced the gene and there are no problems there, how can I still have cystic fibrosis?

Second, he started talking about how complicated CF can be and that in addition to clear mutations, there are some combinations of errors through out the genetic material which can combine to be cystic fibrosis. It even sounded like it could be that these errors could be on other chromosomes . . . Is this true? Or is the genetic material that results in CF only confined to the section of the seventh chromosome that Ambry sequences in their expanded test?

Third, have you found that "atypical cystic fibrosis" is associated with people having weird mutations or lack there of? Apparently the pulmonologist at my clinic expected my results to be weird, because mild cystic fibrosis combined with sweat tests around 100 are not usual. What he was saying made sense at first, but then I thought it was kind of like the use of "reactive airway disease" when they really don't know what is going on. So, is there really such a thing as atypical cystic fibrosis?

Fourth, is there any additional testing on the genetic side that should be done at this point? Or is the answer just we don't know and if the cf clinic pulmonologist thinks that I have cystic fibrosis and i've been responding well to the therapies (which I have), should we just go with it?



New member
Genetics testing


You certainly make some very interesting points. As you probably know by know CF is definitely not straightforward. I would agree with pretty much everything both you and your doctor said, which I know seems to contradict in some places.

First, the CF genetics is just one piece of information and there are people who have CF that have mutations that are undetectable currently. Our most comprehensive testing is 99% so there are still 1% of mutations that are still out there.

There probably are other genes on other chromosomes that can contribute or directly cause CF like symptoms. And this can vary greatly from person to person.

Regarding additional testing, contact me directly at my private email with your name and doctor so I can follow up on what has been done already.

Hope this helps for now.



New member
Just curious, how often do people who have been clinically diagnosed as having CF (i'm guessing this normally means having two positive sweat tests, but I guess nasal differentials, sinus scans and other things could play in) produce no mutations when run through the ampry complete genetic testing? Or turn up only 1?

I guess I'm wondering how often those who are treated at a CF clinic and whose doctors are convinced they have CF and are just getting the genotyping for information are found without mutations?

Is this the kind of thing that has happened once, or is it something that regularly occurs? I know the incidence is dramatically less with the Ambry test, but does it still occur with material frequency?

How many diagnostic tests do you do a year? (in contrast to carrier testing)


New member
I am curious too (about the number/percentage of people with no mutations found with a CF diagnosis with the amplified testing from Ambry) as I know you (Steve) had stated that it is very unlikely not to find two mutations when there are definate symptoms of CF. My son's mutations have not been found (he has had two positive sweat tests).


New member
I'm definitely curious about this. Given a 99% probability of success in identifying a mutation if one is present, it seems that the probability of the test not detecting a single mutation in an individual who has cystic fibrosis should be around .01% or one-hundredth of one percent. The Ambry website says that they've run the full test on 9000 people. Assuming half of these were diagnostive tests being done in individuals who were already diagnosed as having cf (which is a completely random assumption on my part -- i have no idea what percentage of the tests are diagnostive tests and what percentage are carrier tests), this would predict that somewhere around 4.5 individuals who are seen by CF clinics and treated as having CF would not have any mutations show up on the Ambry test.

Seems like there are at least that many who have posted on here! However, I really have no way of knowing what company and what test they received, so it would be very interesting to know how many people or how frequently people who have been diagnosed with CF don't turn up any mutations on the ambry amplified.

The big thing that I'm pondering here is instead of my having CF and just happening to not turn up mutations, I'm wondering if it could be something that operates very similarly to CF, but is not actually CF. I.e. get a positive sweat test and a nice negative number on the nasal potential (took me a bit to get that negative values were positive for diagnostic purposes), but there is some other root cause leading to this same outcome.

Personally, I worry about using the label Cystic Fibrosis if in fact I don't have cystic fibrosis. The clinic was of the opinion that if your symptoms are a dead match for cf and you match with all the diagnostic criterion except the sweat test, then cf is the best way to describe it. However, I'm thinknig that if from a genetic standpoint CF is a disorder of the CFTR protein, then if there are no mutations in the sequencing of that gene, then it can't be cf.


New member
Steve, two bonus question. 1. How are polymorphisms considered in the ambry amplified? 2. The ambry amplified exams all of the exons on the CFTR gene along with the borders of the exons with neighboring introns right? Does it also look at the promoter region of the gene?


Random info I turned up on these questions in case anyone else is interested:

I came across an article which I thought was really interesting dealing with this issue of being clinically diagnosed as CF, but lacking one of the confirmations (it also deals with asymptomatic CFers). It's from 02, so it may be old news to all of you, but it's written such that it's easy to understand and really has been the clearest explanation I've read of diagnosis and management issues with atypical CF. it's at: <a target=_blank class=ftalternatingbarlinklarge href="http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1308781&blobtype=pdf">http://www.pubmedcentral.nih.g...d=1308781&blobtype=pdf</a>

an even older article that might interest you sandra is from 1998 at: <a target=_blank class=ftalternatingbarlinklarge href="http://www99.mh-hannover.de/kliniken/kinderheilkunde/kfg/cf/mekus1998.pdf">http://www99.mh-hannover.de/kl...e/kfg/cf/mekus1998.pdf</a>

From the same site, a case study looking at an individual who suggestions the possible of a single mutation being sufficient to cause CF in some cases (still doesn't answer the no mutations showing up, but interesting): <a target=_blank class=ftalternatingbarlinklarge href="http://www99.mh-hannover.de/kliniken/kinderheilkunde/kfg/cf/bronsveld1999.pdf">http://www99.mh-hannover.de/kl...g/cf/bronsveld1999.pdf</a>


New member
I must say I am very impressed with the level of knowledge on this site. So to address the previous few posts.

First of all most of our testing is diagnostic, probably close to 90%. We do not always receive clinical information on each patient, so it is difficult to know exactly who really has CF and who doesn't. Many times the doctors are trying to rule out CF and when our test is negative that is helpful for them because it confirms their clinical findings.

CF is a very complex disease. There is no one piece of information that can be used out of context. All of the testing, ie. sweat, nasal potential, clinical symptoms, and genetic mutations need to be taken together.

There is very likely to be other genes or combinations of genes that can cause symptoms identical to CF, so you would these patients to test negative for CF mutations.

Regarding using the diagnosis of CF if there are no gene mutations...
You can have one disease caused by different things, it doesn't necessarily change the disease or how you treat it. Diabetes can be caused by CF, or by obesity or by a gene. It is still diabetes but the causes are very different.

I understand the concern and the questions and it just may take more time to more fully understand CF, atypical CF and CF related disease.

I also don't have a specific percentage to give you, but my experience is that there are definitely have patients who clearly have CF with pos. sweat, many symptoms etc. and we do not have two mutations. However, that is not a regular event and the vast majority of patients who present clinically with CF, we do identify two mutations. I think some of the difference may be what some clinic define as CF v. other clinics. But most of it probably has to do with the variability of CF as well as yet undiscovered information regarding CF related disease.

I hope this helps, I doesn't answer all of the questions, but many of the questions just don't have definitive answers yet.



New member
I left out information about the polymorphism questions. This is something that may also change over time, but we do know there are many polymorphisms in the CF gene, these are common variants that not believed to be disease causing.

The Ambry Test does check all exons and the splice sites which are areas around each exon that go into the intron. We report mutations up to 30 base pairs into the intron. However each intron can be many thousands of base pairs and this is not analyzed. This genetic material is spliced out of the gene so most of it is not important. However, there are a couple of known mutation deep in the intron and there are likely to be several more which account for why the test is not 100%.

Yes we do check the promoter region as well.



New member
Steven (Ambry)

Hello Steve,
We have been trying to get a def diagnoses for about 2 yrs now. My
son Steven has had 12 sweat test all on the high end of borderline
so we then had the genzyme test done (i think that's what is was)
test for 86 mutations and then we were told he didn't have any
mutations so there was no way he had cf. and we were also told that
there was no other test to test for any other mutations.So
here we are with new pulm at a university hospital and have
actually been started on pulmozyme and some other meds while
waiting for our ambrey genetics test to come back should be
anytime!!! The new pul said he has many CF symtoms he has the bulky
very smelly feces,thick mucus he can't cough up and erythema all
through his lungs.Numerous boughts of atelactisis and so it just
goes on. I hope everyone out there ill soon know of Ambry genetics.
I wish I had a brochure to take to our old pulm and tell him there
is other testing available!!


New member
Steven (Ambry)


It always surprises me when physicians are not aware of the testing we offer. However, if they dont specialize and tend to see more typical asthma patients, they might not be aware of what is out there. It is difficult for every doctor to keep up on everything. We are always trying to get the word out as well. And we have just made up some patient brochures for our diagnostic tests, if you would like we can send you some. Email your address to my private email and I will have them sent out.

Steven's test is still pending, we received it last week, so it will take a little longer, but results will be faxed to your doctor as soon as they are done.

good luck,



New member
Steven (Ambry)

Hi Steve! I just found out my son's other mutation is Q493X. I already knew that one was deltaF508 but the Ambry test was needed to pick up the other. On the report from Ambry genetics it says it is a deleterious mutation, also on exon 10 of the CFTR gene, and it's considered a severe allele associated with pancreatic insufficiency (my son is pancreatic insufficient). I've since done a little research and now know it is a class I mutation, and I think it is a nonsense mutation resulting in absence of the CFTR protein.

I was just wondering if there's any more information you could give me about the Q493X mutation. I would really like to find out how common (or uncommon) it is. And if you have any info on symptoms associated with this mutation. Basically I'll take anything you've got! Thank you so much for your time!


New member
Steven (Ambry)

Hi Steve. I'm new to the site . . . I just found out that my daughter has the R1158X mutation and can't find much info about it. I guess I have the same questions as Amber (Mallory's other mutation is the F508). Any links you might have would be great.


New member
Steven (Ambry)

COuld u tell me about 1898 +1G >A, what class is it and does it involve a nonsense, splicing, or deletion..


New member
Steven (Ambry)

Sorry it took me awhile to reply, I just got back from the CF meetings in Denver and I am still trying to catch up before I leave town on Friday for the Genetic Counselor meetings.

Regarding the specific mutations. It is really not possible to have a separate clinical history for each mutation. You must all remember that there is variability within each mutation and it also depends greatly on which mutation is on the other chromosome.

Here is what I can tell you, both the R1158X and Q493X are nonsense or stop codon mutations. This means that entire protein is not transcribed and you end up with a truncated protein that does not function normally. These are generally more severe type mutations and often associated with pancreatic insufficiency. (remember there are always exceptions and if the second mutation is a mild one then I would expect them to have a more mild course and be pancreatic sufficient). We have seen both mutations in numerous affected patients who all carried a second mutation (mostly but not all were deltaF508 on the other chromosome). Most patients were typical CF patients, but as you all know that can vary.

Regarding the 1898+1 G>A mutation, this is a splice site mutation, Class I type. Anytime there is a number followed by a plus or minus another number, these are all splice site mutations. Most of these mutation occur at +/- 1,2,3,4,5 however there are some that can occur as many as 26 or 28 base pairs into the intron. Splice site mutations occur in the intron which is spliced out before the DNA is transcribed. Therefore if a mutation in the intron does not affect splicing it will not have an affect on the protein.

This mutation is also one that is seen more often and it is also a typical CF mutation.

Typically there are no reports of each mutation and the effects that is has. Therefore it is not unusual for someone to find very little information about their specific mutation. I hope that helps.



New member
i have a question which has bugged me since i had fought to get my son diagnosed he has 2 double delta f508 genes and im white and my husband is black and i was wondering since the c.f center seemed to think that thats virtually impossible to of happened..why ? my husband has a german grandmother on his moms side? i have been so angry as to why the c.f center acused me of this child not being my husbands but tests proved he was his. Why would the f508 make the c.f doctor think such ignorant things.


New member
I don't blame you for being upset and I really can't answer your question. We see CF in all ethnic groups all the time. It is definitely not as common in the African American and Asian populations but it occurs in every group, just not as often. DeltaF508 is still seen as one of the more common mutations in many other ethnic groups as well.

There are many physicians who still do not think of CF outside of the caucasian populations. As we learn more and more about CF mutations, we are always trying to educate the medical community. As many of you know, sometimes that can be a long process. But we will never stop trying.