I would imagine new interface would entail new controls. It's obvious that hand waving cannot really operate conventional mouse-centric controls in current CAD systems. But new and innovative 3D on-screen tools specifically made to interact with gestures could make it work (becoming more closer to virtual sculpting). As for hand fatigue, muscles could get used to it. Extra supports could also be provided at elbows for regular operations. The first time touch-typing is also exhausting to fingers and wrists.