Could humans change chromosome number again?

It is likely that for a chromosome number change to happen again it probably needs a small population and/or a reproductive advantage in order for the fused chromosome mutation to spread through the population.

A small population looks unlikely in our ever increasingly populated world but either environmental collapse or another world war (with nuclear weapons) could reduce the population dramatically and result in isolated populations. Over time those population's genetics would vary with each population having its own set of unique mutations.

There are no known reproductive advantages for the pairs of acrocentric chromosomes which commonly fuse in modern humans (14,21 and 14,13) but then again we still don't know what reproductive advantage was gained from the fusion of our chromosome 2. Further research may shed light on this as we continue to map the genes which surround the fusion point on chromosome 2 and compare them to our ape relatives. Perhaps one day we will understand why it happened or perhaps it was just random genetic drift.

Finally, to demonstrate that it is possible for a human to have a stable (even) number of chromosomes other than 46 there are at least two cases of 44 chromosome pregnancies. The first in 1982 (Ref 1) did not come to term, but a second one in 1989 (Ref 2) resulted in the birth of a phenotypically normal child. It is likely that there are more examples of humans with differing chromosome counts as only a very small proportion of births are checked for genetic abnormalities, especially if the baby appears normal.

This is living proof that humans can have a chromosome number other than 46. Could the whole population change though? Possibly. Events such as a species changing chromosome number take an unusual combination of circumstances, but given enough time even exceptionally rare events will happen.