Question

1. In McCune-Albright syndrome, fibrous connective tissue replaces bone, tan patches (café-au-lait spots) dot the skin, and hormone abnormalities cause early puberty and malfunction of the thyroid, pituitary, and adrenal glands. The phenotype is highly variable, and all patients are somatic mosaics for the mutation, which is in the gene GNAS1. Why is the condition seen only in mosaics?

2. Explain why designating allelic diseases or terming a mutation a “variant of uncertain significance” is based more on the state of our knowledge than on biological phenomena.

Answer 1

1.- Well, this is because the mutation is an autosomal dominant lethal mutation. When the mutation occurs, the embryo that carries the mutation dies, that's why it is never seen in common individuals. Mosaicism then resulted as the only way for the mutation to actually arise and show in developed individuals.

Mosaicism is the phenomenon when an organism has 2 different types of cells that have different genotypes, this means the individual has 2 different cell populations that formed different parts of its body.

When the GNAS1 mutation occurs in one of these mosaic cell populations but not in the other population (since embrionic development), the individual is able to live but will have some issues (the symptoms mentioned).

That is why the condition can only be seen in mosaics.

2.- Because such practices are the consequence of lack of information/understanding of the genetic processes. Whe you call a mutation a "variant of uncertain significance" you are admitting you just found a genetic variant but you don't know YET what could be the possible consequences of such variation to actual biological functions. When you designate different diseases to mutations in a single gene or region without further explanation about what exact function is changed to lead to each disease, it means we don't have the required understanding of the mutations effects that finally lead to the observed symptoms, thus it is not a biological phenomenon, it is still our lack of understanding