Also, given the events of Murder in Baldur’s Gate, I wonder whether this will be a fresh start with a new protagonist.
Well, the protagonist's story ended in Throne of Bhaal. It's wrapped up. It's done. There's nothing dangling. There are some adventure scenarios and books which go on, like Murder in Baldur's Gate, and they're really ill-advised.
What I'd like to see is the game opening at the docks of Gray Harbor, with Balduran sailing off to Anchorome. You play the warlord-in-chief of the budding settlement and, over time, you defend and build it. Balduran's legacy goes on the walls, which is canon, but they're as yet incomplete and the stone has to come from somewhere, so you need to secure shipments or a quarry. The farmers want it to protect them, but this will delay completion, and mercenary gangs are harassing commerce, which you rely on. Bootstrap adventuring, similar to Crossroad Keep in NWN2 (which I really enjoyed, and could have been fleshed out much more than it was). Meanwhile, the Big Bad is plotting your demise in true Forgotten Realms fashion.
The story of the earliest days of Baldur's Gate get told, the Tax Revolt, the founding of Amn, etc.