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Mutations of the same class or not?

Question
Dear expert,

Everywhere you read about different classes of mutations. I can understand that predictions cannot be made.
But now I was wondering if it matters / makes a difference whether you have two mutations of the same class or 2 mutations from a different class ...
And if 2 same mutations are "better" than two different ones?

Best regards,
Answer
Dear reader,

Thank you for this question. Many patients have indeed a combination of 2 different mutations classes. Generally we can say that the mildest mutation determines the severity of the disease.

Broadly speaking we can say that class 1, 2 and 3 mutations are considered as “severe” mutations. If you have two mutations of this class, you suffer from classic CF with maldigestion and chronic lung infection. As you state yourself, the severity of the disease can differ strongly between these patients. This has more to do with other genetic factors (e.g. genes involved in your immune system), environmental factors and treatment with the CF mutations themselves. Whether you have two times a class 2 mutation (eg F508del / F508del) or a combination of a class 2 and 3/1 (eg D508del / G551D or F508del / G524X) makes little difference. Some studies indicate differences in severity among these classes 1-2-3 but that is not entirely clear yet (especially a more severe course in class 1 mutations).
Class 4 and 5 mutations are usually associated with a milder course and often without maldigestion. Most of these patients have one mutation from classes 4-5, and one mutation from class 1-3. One 'mild' mutation is indeed sufficient to usually have a milder disease course.

Best regards,
Prof. dr. Marijke Proesmans
08.03.2015