Is isolation between user accessible circuits and protective earth necessary for safety?
Some I/Os carry a chassis reference by design, so you can't isolate PE from user signals in the general case

Some types of signal connectors (most notably, audio connectors) carry a chassis ground (instead of a signal ground) by design.  This is quite important for balanced audio interconnects using TRS or XLR connectors; connecting pin 1 on an XLR or sleeve on a TRS connector to signal ground in an audio application leads to what one calls a "Pin 1 Problem", where noise from the cable shield is injected into the signal reference and thus into the device as a whole.

As a result, it is not possible to maintain a general clearance rule between chassis earth/IO reference earth, which is connected to protective earth given that we are talking about a Class I appliance here, and signals, as your I/O protection and filtering devices will need to be referenced to I/O reference earth as well.