I have a number of MEGA 2650 prototype shields, and DUE's. For the most part they work well together, however I came across an issue that when the shield is attached to the DUE, I can no longer connect to the DUE for uploading sketches, or controlling them with firmata devices. I saw this thread a couple years ago, suggesting the 5V/3.3V issues: http://forum.arduino.cc/index.php?topic=389559.0
Oddly enough, if I run it under firmata, I can turn channels on and off using firmata.exe test programs, so some communication via USB is possible.
Any suggestions on why the sheild is disrupting full USB communication with the DUE board?
-additional note - Here's a pic of a setup I tried while debugging, I connected only the lines I needed to the board, and I could upload sketches again, so my hunch is that some channels are incompatible between the MEGA and DUE that are causing the interference. link - Dropbox - IMG_20190224_144657.jpg - Simplify your life