It is a problem for any well-designed application with shortcuts. For they'd make the shortcuts often used to be according to the OS HIG, and a priority to easy to reach keys being also shortcuts often used (in that order). The latter is just part of learning curve (we all grew up with Qwerty, right? right?!) but the latter is an issue for any non-standard Qwerty (depending on how much they differ from Qwerty; which Dvorak does a lot but Colemak and Workman and Azerty and Qwertz already less so).

So what you say counts for any non-standard keyboard. There's always a learning curve. I tried going to 60%, now I settled for 80%/TKL and there are situations where I miss the other 20%, but my (vertical) mouse is in a more natural position. At least with Dvorak, all the physical keys are the same size as a standard Qwerty, so you could just set to Qwerty English-American and be done with it.