What’s in Your LDS Family Tree? Genetics, Variability, Outcomes (September 1, 2020)
46:47-52:27
This is a tough one. I'm trying to figure out. I don't think it's answerable but what are, what are statistical chances for VUS within TGFBR1 gene to be later categorized as pathogenic?
MacCarrick:
明確な回答が難しい質問だと思いますが、TGFBR1遺伝子内のVUS（意義不明変異）が将来、病原性変異に分類される統計学的確率はどのくらいでしょうか？
So we know quite a bit about where mutations happen in the Loeys-Dietz syndrome types one and types, types one and two, TGFBR1 and TGFBR2 genes. There have been pretty good rules that have been developed about where those mutations occur, what are the consequences of those mutations. There are also, there's also the possibility of doing tests in cells outside the body to ask, "Is that mutation causing a problem and how the protein works?" or "Is it not causing a problem?"
Dietz:
LDSの1、2型は、TGFBR1遺伝子およびTGFBR2遺伝子に変異が起こることで発症しますが、これらの遺伝子内で変異が生じる場所やそれにより引き起こされる病態については研究が進められ、明確な規則があることがわかっています。また、細胞を体外に取り出して検査することで、変異が病原性かどうかやできたタンパク質の性質についてもわかります。
So VUSes, variants of uncertain significance, are pretty rare in TGFBR1 and TGFBR2. We can generally exclude the importance of a variant based upon how common that variant is in the general population or about where that variant occurs along the gene: if it's at the very beginning of the gene it's very unlikely to be causing a problem. If it's at the end of the gene it's much more likely to be causing a problem. You know, I can't answer that question precisely about what are the percent chances
Dietz:
TGFBR1遺伝子とTGFBR2遺伝子にVUSがみられることは、かなり珍しいことです。一般集団においてその変異がどれだけの頻度でみられるか、あるいは遺伝子内のどの場所で変異が起きているのか、といったことを基準が遺伝子変異の重要性が判断されます。遺伝子のかなり最初の部分に変異がみられる場合には、問題を引き起こす可能性は非常に低く、遺伝子の最後の方にある場合には、その可能性は非常に高くなります。とはいえ、質問に対して具体的な数字でお答えすることはできません。
But, you know, often a variant is categorized as of uncertain significance by the initial reporting lab but when somebody looks at that variant, who's seen lots of people with Loeys-Dietz syndrome and who's really familiar with the rules about when something is likely to cause a problem or not, they often can come to a very rapid, clear decision about, "No, no, no, that's more likely to be a disease-causing change than VUS," or "that's much more likely to be innocent than VUS." So I think that's the probably the most common way that that issue is resolved to get an opinion from somebody who's very familiar with looking at these types of changes.
Dietz:
変異をVUSに分類するのは、1次報告機関である場合が多いのですが、LDSの患者さんを多く診察し、病原性変異かどうかを識別するルールに精通した方であれば、その変異を見ただけで、多くの場合、病原性かどうかはすぐにわかります。ベストな方法は、VUSのような変異にかなり精通した専門家に意見を求めることだと思います。
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
