Bench-top or welded frame

[JAZZCNC]

My real question is one of opinion - of whether the spindle offset will impact the performance enough to make this design impractical - if you have any thoughts I'd appreciate them.

Well think you could afford to go with something like this setup with you having ball screws on inside and not lose to much travel.
On original design with 100mm wide bearing plates and the gantry going to outside edge the spindle centre line will actually be over the linear bearings or very close. So if you used say 80x40 for the diagonal you would still have room for railbearings and only lose probably 40mm or so of travel.

To be honest I don't think the over hang is massive anyway and provided you build it strong then won't have massive affect. End of the day the extension is still less than most Milling machines.

Personally I'd build a wider door in my shed than compromise the machine.