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Thread: unknown genotype

  1. #1
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    unknown genotype

    I have been sorting through the records I have from clinic and hospitalizations and found a document that lists my genotype 2789+5g->a / unknown
    from what I recall my doctor told me that my mutation was from (discovered?) eastern NC which is interesting since I live in NC, but my inquiry is about the unknown in my genotype, is it common? could this be why they needed a sweat test before they would officially classify me as a Cystic patient?

  2. #2
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    Hi Luna,

    My sons both have one unknown mutation -- So it does happen sometimes. They were both diagnosed on sweat tests +symptoms. Good luck in your search.

  3. #3
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    According to the CFTR2 Database, 971 people have been put in the database that have 2789+5g. With another CF causing mutation you will have CF. In other words, it's a disease causing/contributing mutation. If you Google "CFTR2" and enter your mutation and be sure to press the search tab it will show what else is cataloged. I believe UNC at Chapel Hill is where it is rumored to have been discovered.

    Hope that helps,

    LL
    67yr. old man, DX CF 2002 by sweat test. Heterozygous S1235R revealed by genetic testing in 2003 & 2012 accepted secondary mutation. 7T, 7T polymorphism established to be virulent. Classification review in 2017 remains CF diagnosis.

    Complete pancreatic atrophy, Bronchiectasis, MRSA, osteoporosis, small duct disease, charming personality.

  4. #4
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    I actually go to UNC for my CF treatment so I find that very interesting/amusing. I actually did look up the 2789+5g in the CFTR2 database I found out really only one thing my doctors didn't mention and that's that I'm not likely to be pancreatic insufficient, its the unknown I was curious about but thank you for the information I didn't know the number of people who have my mutation

  5. #5
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    LunaFaith,

    I was surprised that UNC has such a large CF department at their medical school. A rather shy friend of mine asked me to join her for her appointment with a new primary care doctor, who it turns out he graduated from UNC's medical school. He had seen possibly hundreds of CF patients while at UNC, the University Hospital (?) has a lot of beds dedicated to CFers. I was unaware of the significant investment UNC has in CF medicine until then.

    Do you have any idea why there would be so much dedication to CF at UNC? I really don't know. My only hint is the unique accent found in NC, i.e. Jim Neighbors, Andy Griffith two "Gomer Pyle's". I have been told that the accent comes from the Scotch-Irish who emigrated in droves, at different times from Scotland and Ireland. The Scotch's-Irish are among the highest percentage of the world population with the potential for CF.

    Speaking of which I have been in an infectious fog and thank you for graciously pointing out that I missed your two questions completely. Let me try again. I'm vaguely familiar with the population statistics of Ireland and Scotland and something like 1 in 25 people are carriers. I've done the math on this data and there should be something like 6 times as many people with CF as reported. In the U.S. a study of ER pancreatitis patients revealed 170,000 undiagnosed CFers, and due to the restrictions of the study remain so despite the fact that they were diagnosed. Two populations of CFers make up the diagnosed, neonatal/infant diagnosed with CF and an increasings group of late diagnosed adults. I believe that this is effecting the scope of CF genetics, "unknown mutations" in particular.

    When I was diagnosed it was with a sweat chloride test after being told that I held the record for the worst pancreatic function test on record in North America, possibly the world. Two sweat tests were conclusive. Subsequent genetic testing, a comprehensive assay showed a single mutation and a Polymorphism that has subsequently been established as disease related, albeit mild effect. According to the same CFTR2 Database my S1235R mutation isn't disease causing. I've got a handful of research articles that disagree with that conclusion. So where's the beef?

    At the time of my first genetic assay, (2002) less than 250 mutations had been found out of the 3,000+/- discovered or modeled since 2002. This may be why you have an unknown mutation, assumed to be there because the sweat chloride test is still the gold standard. With rare exception, a positive test is CF, and if it's not, a few conditions explain the cause. Very few exceptions have been found. You might not have another mutation, genetic testing doesn't prove a negative, that came out because of the sweat test confirmation that might have been provided to the genetic testing facility. I believe that you indicated that it's the other way around with you, sweat chloride test is usually given first which is the way it logically should be done. My sweat tests ran under $100 each, cash price. It used to be around $3000 for genetic testing and it is logical to have the sweat test first. Depending on when and how comprehensive your genetic testing was, it could be common, being part of a larger group that has been tested before the full list of all mutations were known. There's a lot of sweat test and clinical presentation diagnosed CFers who don't have two known mutations. Currently the main reason for genetic testing is for confirmation of the diagnosis. It's not going to be able to say how severe it's going to be. Genetics will be able to make these determinations, just not yet.

    Unconventional mutations are being discovered that don't meet the criteria currently defined. And, this is why many people have an unknown mutation. I repeated the genetic testing in 2012 when the complete list of mutations were known. Nothing new was found, but they did change the benign polymorphism in my profile to reflect the discovery of its contribution to the disease. I was surprised last year when my doctor alluded to my 7T, 7T polymorphism recently as my known mutation. This would indicate that we're still figuring out the total number of contributing genetic factors affecting CFers. I've known it's potential impact for several years, identified by Ambry Genetics before my doctor brought it up. My polymorphism is an unconventional mutation.

    The flip side is that ~66% of diagnosed CFers make up ∆F508del + ∆F508del with 20% more in three other mutation sets. A mere 3% make up the nearly 3000 mutations that in combination make up millions of unique mutation sets. So roughly 90% of early diagnosed are not going to have an unknown mutation. Oddly enough this data is not congruent with the number of people who have an unknown mutation. This is where the late diagnosed come in. Many people are coming out of the woodwork, seemingly with slow motion CF, a milder form, or maybe a more resilient person is diagnosed late. Many people who would be carriers, with one common mutation and only after discovery of the full list have a second mutation found. I predicted that unconventional mutations would account for a significant number of unknown mutations. They're being discovered. You have several possible reasons why your second mutation is yet to be identified. Repeating the test, depending on how many mutations were known when you were tested, and if it was comprehensive, could reveal the unknown mutation. I wish I could easily tell you how common unknown mutations are assumed. The CF clinic I go to is happy with my genetics compared to my presentation. It's weird that they say that my second mutation has yet to be determined. Maybe you can discover your unknown mutation by repeating genetic testing.

    Your second question as to whether your sweat test was performed to confirm your CF diagnosis, I trust that you were genetically tested prior to having the sweat test. This is something you know is important. That being the case I would say that you are probably correct about why the sweat test was done. I'm not familiar with how neonatal screening is done but it looks like a sweat test is the first confirming test. Sweat tests are somewhat problematic when it's performed on a CFer because our sweat is sticky and viscous, making us bad sweaters.

    I've read countless stories about the doctor wishing to repeat a marginally failing sweat test as many as 9 or ten times, usually done over a a year or two. The reason for what is unorthodox at the least but there's method in the madness. Just one good confirming sweat tests is a direct measure of the CFTR gene function. Poor chloride transport is measured more or less directly and can justify the severity and affected areas. For example, high numbers are often a predictor of the pancreas and GI system being more affected than the pulmonary system.

    Unless one of the the new class of genetic drugs is helpful, genetic testing is moot. The catch 22 is you have to know your complete CFTR analysis in order to determine if anything can or soon will be out that would be useful for you . I realize that I haven't given you a number or a percentage of people who have an unknown mutation. It's not a simple question as it turns out.

    Hope that helps,

    LL
    67yr. old man, DX CF 2002 by sweat test. Heterozygous S1235R revealed by genetic testing in 2003 & 2012 accepted secondary mutation. 7T, 7T polymorphism established to be virulent. Classification review in 2017 remains CF diagnosis.

    Complete pancreatic atrophy, Bronchiectasis, MRSA, osteoporosis, small duct disease, charming personality.

  6. #6
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    I didn't want numbers or percentages so much as to know it's not really rare, its comforting to know that there are others who have an unknown genotype like me.
    on a side note the hospital has a 'floor' in the memorial wing, 6 bed tower that is unofficially the CF floor, I do believe it's referred to as the infectious disease ward, either way the floor has mostly all single rooms since most if not all CFers are on no contact, its pretty hard to find single rooms in any other wing of the hospital

  7. #7
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    I grew up in chapel hill and went to UNC from age 4-27. Had amazing care there. They have a really large cf and lung disease research program with some big names so I would imagine that attracts doctors and fellows to the CF program (both adult and pediatric).

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