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Welcome Ambry Genetics
- Thread starter Buckeye
- Start date
I'd like some information on these two genes: F508 and W1282x.
My 2 week old granddaughter just recieved her lab results back from her newborn screening. It stated there was a high likelyhood that she has cystic fibrosis. With these 2 genes is it still possible that she doesn't? She also recieved her first sweat test a couple of days ago and we are awaiting the results.
Any words of wisdom would be apprecitated. Also if someone could comment on what they know about the symptoms etc. associated with these to genes would be wonderful.
I'm so happy to have found this website!
My 2 week old granddaughter just recieved her lab results back from her newborn screening. It stated there was a high likelyhood that she has cystic fibrosis. With these 2 genes is it still possible that she doesn't? She also recieved her first sweat test a couple of days ago and we are awaiting the results.
Any words of wisdom would be apprecitated. Also if someone could comment on what they know about the symptoms etc. associated with these to genes would be wonderful.
I'm so happy to have found this website!
CFHockeyMom
New member
rnordlnd,
Not trying to hijack the thread here but thought this info would be useful...
Firstly, if your granddaughter has two genes then she has CF. The two genes you listed are very common. Delta F508 is the most common gene and W1282x is the most common gene among Ashkenazi Jews.
Delta F508 is considered a Class II gene. Class II mutations, including F508, complete protein translation but produce an abnormal protein that fails to escape the endoplasmic reticulum. Little or no CFTR reaches the plasma membrane, and the absence of all surface CFTR results in a severe phenotype. It is being increasingly recognized that mutations in unrelated genes can create defective proteins, which fail to traffic properly through the cell. Classically, missense mutations creating an abnormal protein were thought to be relatively benign or less consequential than nonsense mutations (null) or large deletions. This is no longer strictly the case because examples from CF and other inherited disorders demonstrate that a synthesized protein that fails to mature along the normal biosynthetic pathway often becomes quite destructive.
W1282x is considered a Class I gene. Class I mutations lead to defects in the synthesis of stable CFTR mRNA transcripts resulting in absence of the CFTR protein. About half of all mutations in CFTR (encompassing premature termination, exon skipping, aberrant mRNA splicing, and frameshifts) are thought to fall into this class and result in complete loss of CFTR protein/function.
<begin quote>1: Thorax. 2005 Jul;60(7):558-63. Links
Genotype-phenotype correlation for pulmonary function in cystic fibrosis.de Gracia J, Mata F, Alvarez A, Casals T, Gatner S, Vendrell M, de la Rosa D, Guarner L, Hermosilla E.
Department of Pneumology, Hospital general Vall d'Hebron, Barcelona, Spain. jgracia@separ.es
BACKGROUND: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). METHODS: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I-II/I-II, I-II/III-V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. RESULTS: Seventy four patients were included in the study. Patients with genotype I-II/I-II had significantly lower current spirometric values (p < 0.001), greater loss of pulmonary function (p < 0.04), a higher proportion of end-stage lung disease (p < 0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I-II/III, I-II/IV and I-II/V (p < 0.001). CONCLUSIONS: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival.</end quote>
Genotype combinations can provide some insight into clinical outcome but in general they are merely rules of thumb. We have many people here that have the same genes but their clinical outcome varies significantly. Environment, compliance, care, and luck all play a very large part in clinical outcome.
Not trying to hijack the thread here but thought this info would be useful...
Firstly, if your granddaughter has two genes then she has CF. The two genes you listed are very common. Delta F508 is the most common gene and W1282x is the most common gene among Ashkenazi Jews.
Delta F508 is considered a Class II gene. Class II mutations, including F508, complete protein translation but produce an abnormal protein that fails to escape the endoplasmic reticulum. Little or no CFTR reaches the plasma membrane, and the absence of all surface CFTR results in a severe phenotype. It is being increasingly recognized that mutations in unrelated genes can create defective proteins, which fail to traffic properly through the cell. Classically, missense mutations creating an abnormal protein were thought to be relatively benign or less consequential than nonsense mutations (null) or large deletions. This is no longer strictly the case because examples from CF and other inherited disorders demonstrate that a synthesized protein that fails to mature along the normal biosynthetic pathway often becomes quite destructive.
W1282x is considered a Class I gene. Class I mutations lead to defects in the synthesis of stable CFTR mRNA transcripts resulting in absence of the CFTR protein. About half of all mutations in CFTR (encompassing premature termination, exon skipping, aberrant mRNA splicing, and frameshifts) are thought to fall into this class and result in complete loss of CFTR protein/function.
<begin quote>1: Thorax. 2005 Jul;60(7):558-63. Links
Genotype-phenotype correlation for pulmonary function in cystic fibrosis.de Gracia J, Mata F, Alvarez A, Casals T, Gatner S, Vendrell M, de la Rosa D, Guarner L, Hermosilla E.
Department of Pneumology, Hospital general Vall d'Hebron, Barcelona, Spain. jgracia@separ.es
BACKGROUND: Since the CFTR gene was cloned, more than 1000 mutations have been identified. To date, a clear relationship has not been established between genotype and the progression of lung damage. A study was undertaken of the relationship between genotype, progression of lung disease, and survival in adult patients with cystic fibrosis (CF). METHODS: A prospective cohort of adult patients with CF and two CFTR mutations followed up in an adult cystic fibrosis unit was analysed. Patients were classified according to functional effects of classes of CFTR mutations and were grouped based on the CFTR molecular position on the epithelial cell surface (I-II/I-II, I-II/III-V). Spirometric values, progression of lung disease, probability of survival, and clinical characteristics were analysed between groups. RESULTS: Seventy four patients were included in the study. Patients with genotype I-II/I-II had significantly lower current spirometric values (p < 0.001), greater loss of pulmonary function (p < 0.04), a higher proportion of end-stage lung disease (p < 0.001), a higher risk of suffering from moderate to severe lung disease (odds ratio 7.12 (95% CI 1.3 to 40.5)) and a lower probability of survival than patients with genotype I-II/III, I-II/IV and I-II/V (p < 0.001). CONCLUSIONS: The presence of class I or II mutations on both chromosomes is associated with worse respiratory disease and a lower probability of survival.</end quote>
Genotype combinations can provide some insight into clinical outcome but in general they are merely rules of thumb. We have many people here that have the same genes but their clinical outcome varies significantly. Environment, compliance, care, and luck all play a very large part in clinical outcome.
Hi Steve,
I wanted to know what you could tell me about 2622+1G>A? I haven't been able to find out much about this one (and the Dr. at the CF clinic can't tell us anything either). My 3 month old son Max was diagnosed following a positive IRT and after genetic testing, was found to carry G551D along with 2622+1G>A. To date, he is pancreatic sufficient w/no pulmonary symptoms.
Thank you so much!
Angela
I wanted to know what you could tell me about 2622+1G>A? I haven't been able to find out much about this one (and the Dr. at the CF clinic can't tell us anything either). My 3 month old son Max was diagnosed following a positive IRT and after genetic testing, was found to carry G551D along with 2622+1G>A. To date, he is pancreatic sufficient w/no pulmonary symptoms.
Thank you so much!
Angela
StevenKeiles
New member
Sorry I have not been able to respond for awhile as I was out of town for family matters.
Michelle,
Regarding 1540A>G this is also known as M470V and this is a very common variant that is carried by almost half the population, so it is not unusual for people to have two copies. these are not CF disease causing mutations.
rnordlnd,
I think Claudette pretty much answered your questions, nice job Claudette.
Steve
Michelle,
Regarding 1540A>G this is also known as M470V and this is a very common variant that is carried by almost half the population, so it is not unusual for people to have two copies. these are not CF disease causing mutations.
rnordlnd,
I think Claudette pretty much answered your questions, nice job Claudette.
Steve
StevenKeiles
New member
Angela,
The 2622+1 G>A is a pretty typical CF disease causing mutation, often associated with pancreatic insufficiency if the other mutation is also severe. With G551D, I would imagine it could go either way.
One other comment regarding the deltaF508 and W1282X, these mutations would always be expected to cause classic CF. Of course some people are not as severe as others.
I hope that helps.
Steve
The 2622+1 G>A is a pretty typical CF disease causing mutation, often associated with pancreatic insufficiency if the other mutation is also severe. With G551D, I would imagine it could go either way.
One other comment regarding the deltaF508 and W1282X, these mutations would always be expected to cause classic CF. Of course some people are not as severe as others.
I hope that helps.
Steve
NFitzgerald
New member
Steve,
I was wondering if you could give me any information about my son's mutations. Delta F508 (which I realize is the most frequently occuring mutation, class 2) and DI507 (which noone really knows much about in our clinic). Any information you could give me would be appreciated.
Thank you
I was wondering if you could give me any information about my son's mutations. Delta F508 (which I realize is the most frequently occuring mutation, class 2) and DI507 (which noone really knows much about in our clinic). Any information you could give me would be appreciated.
Thank you
StevenKeiles
New member
Nicole,
The deltaI507 is a mutation that is probably very similar to deltaF508. I would expect people with these two mutations to be similar to those with two deltaF508 mutations,
steve
The deltaI507 is a mutation that is probably very similar to deltaF508. I would expect people with these two mutations to be similar to those with two deltaF508 mutations,
steve
Genetics testing
Hi Steve,
As I mentioned to you last Spring, my sweat test was negative and I got my genetic results back for the 12 mutations tested and all were negative. Those checked were as follows, based on the fact that I am an Ashkenazi Jew ...
1717+1G->A
3849
D1152H
G542X
N1303K
W1282X
delF508
405+1G->A
G85E
S549R
W1089X
5T
I have been unable to convince the doctors to pay for an Ambry test and I am considering paying out of my own pocket. My question to you is, if the Ambry is negative does that rule out CF completely? Do you have any statistics about Ashkenazi Jews with two rare mutations?
Just to remind you of my background ..
I am a woman in my 40s and have had pneumonia 5 times. The last time was 3 years ago, and it included a partially collapsed lung and it knocked me out for several months and I even broke a rib from the coughing. Ever since then I have had problems with chronic sinusitis, shortness of breath, chest pain, and in general feel horrible most of the time. I cough but don't usually bring up phlegm, except when I have an acute illness - bronchitis or sinusitis. I am and have alway been extremely thin, but have never had any digestive problems.
My doctors (including a leading pulmonologies where I live) have tested me for zillions of things but have found nothing except bronchiectasis and chronic sinusitis. Nebulizer treatments and 7 months of antibiotics didn't resolve the situation. Out of frustration I stopped taking all meds for 6 months and my FEV1 dropped from 89% to 78%. Now I am on seretide (diskus) and flixonase and have gotten the FEV1 up to 85%. I walk 3 or 4 times a week for more than an hour except for the times when I feel too terrible to move.
Thanks for your help!
Hi Steve,
As I mentioned to you last Spring, my sweat test was negative and I got my genetic results back for the 12 mutations tested and all were negative. Those checked were as follows, based on the fact that I am an Ashkenazi Jew ...
1717+1G->A
3849
D1152H
G542X
N1303K
W1282X
delF508
405+1G->A
G85E
S549R
W1089X
5T
I have been unable to convince the doctors to pay for an Ambry test and I am considering paying out of my own pocket. My question to you is, if the Ambry is negative does that rule out CF completely? Do you have any statistics about Ashkenazi Jews with two rare mutations?
Just to remind you of my background ..
I am a woman in my 40s and have had pneumonia 5 times. The last time was 3 years ago, and it included a partially collapsed lung and it knocked me out for several months and I even broke a rib from the coughing. Ever since then I have had problems with chronic sinusitis, shortness of breath, chest pain, and in general feel horrible most of the time. I cough but don't usually bring up phlegm, except when I have an acute illness - bronchitis or sinusitis. I am and have alway been extremely thin, but have never had any digestive problems.
My doctors (including a leading pulmonologies where I live) have tested me for zillions of things but have found nothing except bronchiectasis and chronic sinusitis. Nebulizer treatments and 7 months of antibiotics didn't resolve the situation. Out of frustration I stopped taking all meds for 6 months and my FEV1 dropped from 89% to 78%. Now I am on seretide (diskus) and flixonase and have gotten the FEV1 up to 85%. I walk 3 or 4 times a week for more than an hour except for the times when I feel too terrible to move.
Thanks for your help!
StevenKeiles
New member
Genetics testing
Hi Nervous,
It is unlikely that you would not have at least one of those mutations, but I have seen other patients with two mutations that are not on that list. It is hard to put a number on it, but I certainly don't think that since your test was negative that is rules out CF.
However, if the Ambry Test was negative that would make the likelihood of CF extremely small.
Steve
Hi Nervous,
It is unlikely that you would not have at least one of those mutations, but I have seen other patients with two mutations that are not on that list. It is hard to put a number on it, but I certainly don't think that since your test was negative that is rules out CF.
However, if the Ambry Test was negative that would make the likelihood of CF extremely small.
Steve
Genetics testing
Steve,
I posted this as a new topic and was advised to post here to get an answer from you, so here goes: My grandson was just diagnosed with CF based on the presence of two mutations on a positive NBS, although his Sweat Test was "normal". The test showed R117H/R117H. The MD told my son and his wife that it was rare to see this same mutation in one person and did not know what treatment, if any, would be recommended at this time. Don't know if the initial test was done by Ambry. I have done some research and also recieved a little information from a mom who has kids with DF508/R117H.
I found a gentleman who posted around 3/2007 on here who is double R117H with little or know symptoms. I know that there are varying degrees of severity and range of symptomsw depending on the individual.
Can you give me any information? My grandson is asymptomatic at this time. However, he is only a month old. We are all extremely anxious and shocked right now. Any information would help me understand better what we are dealing with. I am a Critical Care RN and have some experience with CF patients who present with severe pulmoinary problems, but know very little about the different classes of mutations, poly T variations, etc.
Thanks so much,
Ally
Steve,
I posted this as a new topic and was advised to post here to get an answer from you, so here goes: My grandson was just diagnosed with CF based on the presence of two mutations on a positive NBS, although his Sweat Test was "normal". The test showed R117H/R117H. The MD told my son and his wife that it was rare to see this same mutation in one person and did not know what treatment, if any, would be recommended at this time. Don't know if the initial test was done by Ambry. I have done some research and also recieved a little information from a mom who has kids with DF508/R117H.
I found a gentleman who posted around 3/2007 on here who is double R117H with little or know symptoms. I know that there are varying degrees of severity and range of symptomsw depending on the individual.
Can you give me any information? My grandson is asymptomatic at this time. However, he is only a month old. We are all extremely anxious and shocked right now. Any information would help me understand better what we are dealing with. I am a Critical Care RN and have some experience with CF patients who present with severe pulmoinary problems, but know very little about the different classes of mutations, poly T variations, etc.
Thanks so much,
Ally
StevenKeiles
New member
Genetics testing
Ally,
Congratulations on the birth of your grandson. Regarding the R117H mutation, it is a mild (relatively common) mutation. When the R117H has a 5T with it, it becomes a more significant mutation. Therefore, if there are one or two 5T's it would tend to cause more problems. However, if there is no 5T, (only 7 or 9, most likely 7 goes with R117H if not the 5), then I would expect little to no symptoms.
Certainly some mild pulmonary problems could develop now or not for many years. It is definitely helpful to know this so should he develop any problems his CF status would be known and appropriate follow up and care can be given.
I hope that helps.
Steve
Ally,
Congratulations on the birth of your grandson. Regarding the R117H mutation, it is a mild (relatively common) mutation. When the R117H has a 5T with it, it becomes a more significant mutation. Therefore, if there are one or two 5T's it would tend to cause more problems. However, if there is no 5T, (only 7 or 9, most likely 7 goes with R117H if not the 5), then I would expect little to no symptoms.
Certainly some mild pulmonary problems could develop now or not for many years. It is definitely helpful to know this so should he develop any problems his CF status would be known and appropriate follow up and care can be given.
I hope that helps.
Steve
Genetics testing
I had a full panel gene test done by Ambry Genetics in 2006. Under the genetic result it says Cystic fibrosis 508 whole blood.
Now I have been dx with CF becuase I have an M470V and a gene on 7t/9t variant. My case is very much affecting my digestive system and lungs. and is M470V a new gene thats what I was told?!
I had a full panel gene test done by Ambry Genetics in 2006. Under the genetic result it says Cystic fibrosis 508 whole blood.
Now I have been dx with CF becuase I have an M470V and a gene on 7t/9t variant. My case is very much affecting my digestive system and lungs. and is M470V a new gene thats what I was told?!
Genetics testing
Hi Steve,
I would like some information on the mutation L206W. I Would like to know what class it is and any other information you could give me.
My boyfriend has just been diagnosed this year at 35 with CF. He is pancreatic sufficient and have some bronchiectasies. He has d508 mutation and L206W. I know d508 is the most common one, but I would like to know more about the other one.
Thank you
Hi Steve,
I would like some information on the mutation L206W. I Would like to know what class it is and any other information you could give me.
My boyfriend has just been diagnosed this year at 35 with CF. He is pancreatic sufficient and have some bronchiectasies. He has d508 mutation and L206W. I know d508 is the most common one, but I would like to know more about the other one.
Thank you
StevenKeiles
New member
Genetics testing
Aka2007,
We do not consider the M470V a disease causing mutation. It is a very common variant that is seen in about half of the population. Also the 7t/9t are normal variants as well.
RVM1212,
The L206W is known mutation that we have seen many times. Most people with this mutation and a deltaF508 are a little more mildly affected. Some can have more symptoms than others, but usually not the most severe disease with these mutations.
Steve
Aka2007,
We do not consider the M470V a disease causing mutation. It is a very common variant that is seen in about half of the population. Also the 7t/9t are normal variants as well.
RVM1212,
The L206W is known mutation that we have seen many times. Most people with this mutation and a deltaF508 are a little more mildly affected. Some can have more symptoms than others, but usually not the most severe disease with these mutations.
Steve
M
MommyJen
Guest
Genetics testing
Hi Steve,
I am wondering if you can tell me if Genzyme does similar testing to Ambry? My daughter just had testing through Minneapolis Children's and they send out to Genzyme. When I asked my pediatrician about whether my daughter received a short panel or full sequence she didn't seem to have an answer. She suggested that I speak with the pulmonoligist my daughter is scheduled to see later this month even though she was the ordering physician. I am also wondering if ethnic background really plays that big of a part in detecting a mutation? After reading pieces of this thread I see that it is mentioned here and there. When the hospital called to do a pre-admission for my daughters testing they asked, but I don't believe it was used for the test as she stated I didn't have to answer if I didn't want to. Also, after discussing whether my daughter should be classified as Pacific Islander (myself) or caucasion ( my husband) she decided to just enter caucasion, so really no specifics were dicussed. Does this make testing less accurate?
Thank you in advance for answers you may have!
Jen
Hi Steve,
I am wondering if you can tell me if Genzyme does similar testing to Ambry? My daughter just had testing through Minneapolis Children's and they send out to Genzyme. When I asked my pediatrician about whether my daughter received a short panel or full sequence she didn't seem to have an answer. She suggested that I speak with the pulmonoligist my daughter is scheduled to see later this month even though she was the ordering physician. I am also wondering if ethnic background really plays that big of a part in detecting a mutation? After reading pieces of this thread I see that it is mentioned here and there. When the hospital called to do a pre-admission for my daughters testing they asked, but I don't believe it was used for the test as she stated I didn't have to answer if I didn't want to. Also, after discussing whether my daughter should be classified as Pacific Islander (myself) or caucasion ( my husband) she decided to just enter caucasion, so really no specifics were dicussed. Does this make testing less accurate?
Thank you in advance for answers you may have!
Jen
StevenKeiles
New member
Genetics testing
Jen,
The ethnic background has not impact on the test results, it is used more for statistically purposes. We do all the testing for both Children's of Minneapolis and St. Paul so it is very possible that the test came to us. Contact me privately with your daugthers name and I can check.
Steve
Jen,
The ethnic background has not impact on the test results, it is used more for statistically purposes. We do all the testing for both Children's of Minneapolis and St. Paul so it is very possible that the test came to us. Contact me privately with your daugthers name and I can check.
Steve
concernedmom
New member
Genetics testing
Nervous1, I was just wondering if you'd been tested for primary ciliary dyskinesia? It has similiar pulmonary symptoms as CF (plus chronic sinusitis and ear problems.)
Nervous1, I was just wondering if you'd been tested for primary ciliary dyskinesia? It has similiar pulmonary symptoms as CF (plus chronic sinusitis and ear problems.)
StevenKeiles
New member
Genetics testing
For everyone's information, we recently started offering a genetic test for primary ciliary dyskinesia. It can be ordered through your doctors office, the same as the CF test.
Steve
For everyone's information, we recently started offering a genetic test for primary ciliary dyskinesia. It can be ordered through your doctors office, the same as the CF test.
Steve