Best thing to do is grab a piece of cardboard and do a layout that way first. For spacing, just markup where your hands naturally rest gripping the joystick and buttons.
Regarding ergonomics, I've found only the first row of buttons needs to be slightly lower. Rows two and three should be the same height. Reason is that when your hand is resting on buttons, the fingers actually rest in a mostly straight line. Usually the index finger is a little lowr, but the second and third finger end up being the same height. Try it with a piece of paper.
As far as drilling, you have it right. Just print out the layout, tape it in place, use something sharp to mark the centers of the buttons/joystick, then drill it out.
For height on the panel itself, I find leaving at least 4 inches of space from the lowest button to the bottom of the panel is adequate.