Do you have a gamepad you can try?
Can you use Bootcamp to try the Windows or Linux version?
Are you shutting down all non-essential programs before starting the game, especially anything mouse related?
Are there any mouse accessibility or compatibility options you can try enabling, changing or disabling?
Someone else recently reported this starting to happen after they got a new mouse and updated Sierra from 10.12.5 to 10.12.6. It has been reported a couple other times, though to a lesser extent (only clicking through parts of the UI, or only if there was something behind that could be interacted with).
Try disabling the deferred renderer for the game; that helped some people with input lag in D:OS Classic. It is more likely to cause a crash on startup than help, but it's easy to change back if so.
In the '..\Documents\Larian Studios\Divinity Original Sin Enhanced Edition\graphicSettings.lsx' file, search for the term 'RenderDeferred', and in the second row after that, change the one to a zero, and save the file.
<attribute id="MapKey" value="RenderDeferred" type="22" />
<attribute id="Type" value="0" type="5" />
<attribute id="Value" value="1" type="4" />
