Can someone explain in plain English

[suren]

My son's genetic test says

The individual is heterozygous for the p.T8961 (c2687>c) variant of unknown significance in the CFTR gene................ The individual carries the 7T/7T poly T variants in the CFTR gene.

Can someone explain in everyday language what the above means. I could not quite follow what the geneticist said to me.

Thank you very much.

Suren

 

[LittleLab4CF]

Suran,

I'm not familiar with the first mutation, and it's possible that somehow you have the 2 names for it have an error, like a misplaced or wrong letter or number. After searching several databases, I can't find it. I have information on the 7T but I'm afraid I need your help. Any chance you could double check the mutation identification and report what you find?


LL

 

[suren]

Suran,

I'm not familiar with the first mutation, and it's possible that somehow you have the 2 names for it have an error, like a misplaced or wrong letter or number. After searching several databases, I can't find it. I have information on the 7T but I'm afraid I need your help. Any chance you could double check the mutation identification and report what you find?


LL

Thank you very much for your reply. I think I made an error. The correct write up is: This individual is heterozygous for the p. T8961(c.2687C>T) variant of unknown significance in the CFTR gene, which may or may not be contributing to this individual's clinical history. This result decreases the likelihood, but does not eliminate the possibility, that this individual's clinical condition is due to to alternations in the CFTR gene.

This individual carries the 7T/7T poly T variants in the CFTR gene.

I would really appreciate it if you could explain what the above means.

CFTR Full Gene

Pathogenic Mutations: None Detected
Variant, Unknown Significance: p.T8961
Poly T Variant: 7T/7T

Gross Deletion(s)/Duplication(s): None Detected

 

[LittleLab4CF]

Thanks for noting the exact wording. I was able to locate it in the CFTR Database and it has been analyzed as to it's biochemistry but I'm not coming up with any research on how it operates, or impacts the patient . With ~2,000 CFTR mutations and now polymorphisms​ like 7T/7T and such, the genetic combinations​ have expanded geometrically. The virulence of the variant is going to be seen in your son and he may be the first. The most common and the worst mutations have been a priority and hopefully that means he's not going to have issues because they haven't gotten to it.

More important is his heterozygous status, meaning that he has just one mutation, or variant as they call it. Understand that nothing is absolute in genetics. In the majority of people who have CF, they have a mutation, or something acting like one, plus another mutation. In classic terms, having the same mutation on both chromosomes​ is homozygous, and is most likely to come with CF issues. We know now that a different CF causing mutation on each of the two chromosomes​ has a good chance of causing CF. I'm referring to the pairs of chromosomes in each cell.

The 7T/7T polymorphism is known to cause CF of the pancreas and GI tract. He could be a symptomatic carrier, a heterozygous patient with less severe symptoms because of the polymorphism. It's not overly common, but worth keeping it in mind.

I know that you wanted this in plain English. I'll try. Your son has a single copy (heterozygous) of a CFTR mutation T8961, a variant of unknown disease causing ability. It appears that a Poly T variant 7T/7T is associated with this mutation.

I know that a few CFers present pancreatic and GI issues with T polymorphisms​. If you have a symptom free child, file this away and move on. Someone thought this was an important test. If he's symptomatic, I'd like to know what is going on. I'm 7T/7T.

LL

 

[Nell]

I can help, I am a geneticist. First, your mutation is T896I, not T8961. 896 is the amino acid number of CFTR that is affected. Proteins start with amino acid #1 which is always a methionine, and are numbered sequentially to the stop codon at the end. Each amino acid is encoded by three nucleotides. Although the 'languaged of life' is composed of only four nucleotide letters; G, A, T and C, these nucleotides are read in 'words' of threes to create amino acid sequences. There are 20 different possible amino acids that are used to make proteins. The C to T nucleotide change at nucleotide position 2687 of the DNA sequence causes, when read in groups of 3 starting at the initiator methionine (position 1) a different amino acid to be encoded at amino acid 896. Isoleucine (I) instead of Threonine (T) is the result. You can see that 2687 is roughly divisible by 3 to give the amino acid position.
The 7t allele is a a mutation in the intron (noncoding) portion of the gene which nonetheless affects splicing. There are three versions of the Intro 8 splice site (5T, 7T, and 9T). The 9T allele is the normal allele and gives efficient splicing to include exon 9 in the CFTR transcript. The efficiency decreases with shorter runs of T at this position (5T and 7T), which results in a lower than normal level of CFTR that contains exon 9 as it should. So it appears that both your alleles are 7T, which means your T896I also occurs on the same chromosome as 7T. When 2 mutations are carried together on one chromosome they are said to be 'in cis'. When they are on the opposite chromosomes, it's called 'in trans'. This mutation is called a missense mutation because it changes an amino acid. A nonsense mutation changes a coding amino acid to a stop codon which truncates the protein prematurely.

When two copies of 7T are carried (one on each chromosome) then very little CFTR containing exon 9 is made.

 

[HuntersmomTBM]

Hello Suren,
(I tried this earlier but it didn't post)
My son is almost 19 he was diagnosed with CRMS - Cystic Fibrosis Related Metabolic Syndrome at 14 because his genetic test found 7T/7T. Hunter was born with Tracheobronchomalaica (a floppy airway) so everyone thought his respiratory issues were all related to his TBM. We later found his TBM was resolved. Hunter's history is 2 RSV's, 9 pneumonia's, 7 bronchitis', 16 croup's, countless upper respiratory and sinus infections. He had failure to thrive as a toddler. He had trouble with constipation or diarrhea. He had 2 sweat test both borderline. He does an airway clearance vest, pulmozyme, atrovent, hypertonic saline soluation, flovent, zenpep and steroids and antibiotics as needed.

 

[suren]

LL,

Thank you very much for your reply. You are both helpful and knowledgeable. The best thing about you is that your are 66 years old -- reading about your age gives hope to people like me.

My son has had respiratory issues but no GI issues, which is odd given that you are saying that 7T/7T comes with GI problems. There are so many variables at play here that it is very confusing in trying to to figure what is going on in any particular case.

I am wondering if it would be possible to PM you to find out a little more about this.

Thank you.

Suren

 

[suren]

Nell, thank you very much for taking the time to explain in great detail. Your explanation is a little technical and I am not able to reconcile it with the Ambry Report that says:This result decreases the likelihood, but does not eliminate the possibility, that this individual's clinical condition is due to to alternations in the CFTR gene. Please share your thoughts.

Thank you again.

Suren

 

[suren]

Thank you Huntersmom. I have had my son's doctor talking about CF type diseases but he never strayed away from CF diagnosis. I guess because my son has a clear positive sweat test.
LL just wrote that 7T/7T is more related to GI problems but your son has a lot more respiratory issues. Has any mutation been identified in his case?

My son has three staples: vest, Pulmozyme, and Albuterol. Been on Tobi twice.

 

[DanfromIL]

Hi Suren -

The response above are far more technical than I am about to be. I would just add that you should be sure you are taking your son to a CF Foundation-approved care center so that he is being treated by CF specialists and not just a run-of-the-mill pulmonologist. I am guessing you are already doing that. Then just do what your doctor tells you. The doctors and nurses at CF Centers are excellent. Your son, if he keeps up with taking the medicines and therapies your doctor prescribes, has every expectation of leading a long and productive life. Of the children in my family, 3 out of 5 were diagnosed with CF. My sister (the oldest) only lived to be 13 due to the delay in being diagnosed. She got pneumonia twice as a young child, and they also didn't know then how to help kids with CF gain weight. But my brother and I are now 51 and 50 years old and doing well. I would guess that in 15 years there will be a virtual cure of CF. So have your son take care of himself now. Once the cure comes along, he'll probably live the rest of his life with his lungs at the state where they are when the cure comes. So if he can keep strong pulmonary function til then, he'll be in great shape. Make sure he eats a lot and takes the necessary digestive enzymes; and get him out there exercising. Developing strong lungs through sports that emphasize aerobic exercise (like running, swimming, etc.) will help keep his lung function high. The motto you might want to adopt is that "CF is trying to kill you, but you don't have to let it. The medicines and therapies work great. If you attack it, you will win." Best wishes.

 

[suren]

Hi Suren -

The response above are far more technical than I am about to be. I would just add that you should be sure you are taking your son to a CF Foundation-approved care center so that he is being treated by CF specialists and not just a run-of-the-mill pulmonologist. I am guessing you are already doing that. Then just do what your doctor tells you. The doctors and nurses at CF Centers are excellent. Your son, if he keeps up with taking the medicines and therapies your doctor prescribes, has every expectation of leading a long and productive life. Of the children in my family, 3 out of 5 were diagnosed with CF. My sister (the oldest) only lived to be 13 due to the delay in being diagnosed. She got pneumonia twice as a young child, and they also didn't know then how to help kids with CF gain weight. But my brother and I are now 51 and 50 years old and doing well. I would guess that in 15 years there will be a virtual cure of CF. So have your son take care of himself now. Once the cure comes along, he'll probably live the rest of his life with his lungs at the state where they are when the cure comes. So if he can keep strong pulmonary function til then, he'll be in great shape. Make sure he eats a lot and takes the necessary digestive enzymes; and get him out there exercising. Developing strong lungs through sports that emphasize aerobic exercise (like running, swimming, etc.) will help keep his lung function high. The motto you might want to adopt is that "CF is trying to kill you, but you don't have to let it. The medicines and therapies work great. If you attack it, you will win." Best wishes.

Thanks a lot. He goes to a topnotch CF Center in NYC. It just feels wonderful to hear from CF patients who are in their 50s. My best wishes for many more years of a healthy life for you and your brother.