Variable Expressivity

So far, even if the situation looks complex, the underlying concepts make sense. Different mutations in a gene may produce a different phenotype because the two mutation types are having very different functional effects on the resulting protein. A gene in which an absent essential is associated with a trait is not thereafter limited to mutations that remove its activity or eliminate its gene product. It is still free to mutate in a fashion that creates a few monkey wrenches or to take on some new function for which we might not be able to predict the trait. So it makes sense that different mutations in the same gene might do very different things. Different mutation types in the same gene may produce very different traits because the two mutation types have very different functional effects on the resulting gene product, with one type of mutation causing a gain of function and another type of mutation in that same gene knocking out the protein's ability to carry out its function.

What is harder to understand is the level of variation in phenotype within a given trait that we can see between individuals whose disease is caused by exactly the same mutation. We use the phrase variable expressivity to refer to the situation in which different individuals with the same disease-causing mutation show quantitative or qualitative differences in the severity of the trait. Let's take the example of a family in which everyone affected with glaucoma has a Val426Phe MYOC mutation. A total of twenty-two members of this family have glaucoma caused by the Val426Phe mutation. The average age at which glaucoma was diagnosed in this family is twenty-six years of age, which is decades earlier than the age at which the common forms of glaucoma usually turn up. One of the most obvious signs of variable expressivity in this family is the great variation in the age at which the disease first manifests itself. The earliest age at which anyone was diagnosed was age sixteen, and the latest diagnosis was at age forty-six. One individual with the Val426Phe mutation still had not developed the disease by the time she was sixty, although she was starting to show faint signs that she might eventually become affected.

When we look at other MYOC mutations, we see a similar pattern: the average age at which the disease starts is young, but there is a big difference in the age at diagnosis of different individuals with the same mutation. Table 29.1 shows information on when glaucoma was first diagnosed in six families with six different MYOC mutations. When we look at the last mutation in the table, we see the amazing range of four to eighty years of age. If we look further at what we know about each of these families, we discover that the family with the Ile477Asn mutation is an enormous kindred with almost a thousand known members, including seventy-four affected individuals spread across eight generations. So perhaps the phenotypic effects of this mutation are really even more variable than the others, but we have to wonder if we were to look at a comparably large number of individuals with each of the other mutations whether we would find a similarly large range of ages. We also have to wonder whether we are looking at identity by descent, or whether there could be one or more additional glaucoma genes playing a role in a family this large.

Some information makes us think that there are real differences in the phenotypes associated with these different mutations. One missense mutation that replaces the proline at position 370 with leucine causes a very early onset form of the disease. If we compare the Pro370Leu family from Table 29.1 with other known Pro370Leu families around the world, we can confirm that this is on average the earliest of the known MYOC mutations. Also, if we compare

TABLE 29.1 MYOC Mutations Show Great Variation in the Age at which Glaucoma is First Observed in six Families

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