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Many genetic diseases are caused by mutations in a gene and often, it is a single nucleotide polymorphism (SNP) that has dramatic consequences (e.g. the E6V hemoglobin mutation in sickle cell disease). Other diseases are the result of multiple mutations, that have occurred within various genes (often in cancer).

My question is, are there also many (or any?) known diseases that only manifest if two or more particular mutations arise in the same gene? My assumption is that they exist, but are rather rare; an ideal answer would point me to a publication with quantitative data: how many known diseases are caused by a single mutation, how many by double, etc.

Regarding alleles: I am not asking whether mutations have to occur homozygously to manifest; I'm talking about mutations in the same copy of the gene; for coding sequences, we would be talking about a double (triple,...) mutant of a protein.

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    $\begingroup$ I doubt that such data exist: it would mean a) enumerating all the possible (genetic) diseases, and b) knowing exactly what kinds of mutations are responsible for each of them. There may be also ambiguity in defining what are different diseases and what is not - liek in the case of cancers. $\endgroup$
    – Roger Vadim
    Sep 6, 2021 at 15:16
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    $\begingroup$ Would Huntingtin mutations fit? $\endgroup$
    – bob1
    Sep 7, 2021 at 9:26
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    $\begingroup$ @RogerVadim OMIM is a good database for that but one would have to look at specific diseases. However, I didn't a table of mutations and the associated diseases. $\endgroup$
    – WYSIWYG
    Sep 8, 2021 at 14:41

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I think that this question cannot be quantitatively answered, because the baseline "non-disease" state is not well defined.

Let's take as a starting point the example that you gave, of sickle cell disease. It turns out there is not actually a single mutation that can lead to the disease, but a number of different mutations. A person with only one of the two copies of their hemoglobin genes affected will be a carried but will not have a sickle cell disease. A person who is affected in both copies will have some form of sickle cell disease, though the specifics will depend on the mixture of mutations present. Does this count as one or two mutations? Would it be counted differently if each copy has the same mutation or a different mutation? What about for the carriers, who have the same mutations, but not the disease?

For another example, consider the case of BRCA1. A person with this gene disabled is highly susceptible to cancer. Should this be counted as a mutation that causes a disease, or should only the mutations on the path to the cancer itself?

It only gets worse when we start considering more complicated questions of susceptibility and potential risk, such as associations between SNPs and heart disease, where the causal relationship becomes extremely murky indeed.

Bottom line: I think that biology has too much fuzziness for a crisp answer to this question in this form.

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  • $\begingroup$ Updated question to clarify alleles; but question is clear: "are there diseases that only manifest if two or more mutations arise in the same gene". Yes, sickle cell can also manifest with >1 mutation, but one suffices --> not an example of a disease that only manifests if there are >1 mutations. Arguing about disease definitions is also not helpful; there are ressources online that define diseases e.g. here. Ok, there's no IUPAC defintion, but that's okay. For any given definition of a disease: how often are they caused by double mutants? $\endgroup$
    – Anonymous
    Sep 7, 2021 at 7:33
  • $\begingroup$ @Anonymous I still think the concept is ill-defined, because you can't distinguish between "gene with one of two mutations required for disease" and "gene requiring only one mutation for disease" $\endgroup$
    – jakebeal
    Sep 7, 2021 at 9:08

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