As far as classes and player characters, I'm likely going to keep the DA classes. In the video games you're playing the great, unique, destiny-ed hero, so you're able to do anything and/or everything whereas every other character in the world falls into one of the three more traditional roles. For a tabletop version I think a limited class system would work best, possibly adding in three mixed-classes (Warrior-Rogue, Rogue-Mage, and Warrior-Mage) Where the player would have to select which aspect was more dominant; ie, is he/she a big dumb warrior who can sneak, or a sneaky, backstabbing rogue who can hold his own when getting stuck-in? A Mage who can pick locks, or a warrior who freezes their opponent?
Taking a warrior as the dominant side, it would mean reduced health and less weapon groups in exchange for beginning with a single spell and a small amount of mana/magicka (say, 1d3+(magic/2)).When given the option to acquire a new level in a talent, the character could instead choose to select a new spell, and at each level would gain an amount of mana/magicka equal to their magic stat.
As for focuses/skills, perhaps three levels would work best instead of five (Novice, Journeyman, and Master, at +1,+2, and +3 respectively). I don't like the idea that, no matter how long a character is out doing his/her thing, they only ever get +2 from a focus. Stat increases help mitigate this, but then again I don't like the 'all focuses go up by one/no focuses go up by one' mechanic of it. For them, with differing levels, when a character could gain a new focus they could instead increase a currently possessed focus by one level so long as they had a base stat of the appropriate level.
A lot of the spells from DA could be imported easily enough, but there would need to be a slew of new ones added (Bound items and summoned creatures immediately come to mind, as does Muffle). The DA focuses of Spirit, Creation, etc would be replaced with the TES schools (Alteration, Conjuration, etc). The magic system would likely see the least amount of tinkering.
Whole slew of monsters and enemies would need to be added, but the biggest challenge will be importing the alchemy system.
Weapons and armor would also need to be tweeked, though not by much; in fact, it might be easier to make weapons and armor made of certain materials (ebony, for example) work off of the DA 'they're rare as hell so getting one is a big deal' system.
Some of the DA specializations would likely get tossed, with new ones added in based upon the factions in the game world.
The setting would likely be after the events of Skyrim, though I'm a fan of the pre-Thalmor Invasion world myself.
PS: @shonuff I hear ya. One of my houses (Hjerim) has Calixto permanently inside of it, and he tries to kill me every time I set foot inside. He goes down after a hit or two, but it's still aggravating that I can't kill him because the quest glitched. Oh, and I can't complete the Stormcloaks side of the civil war since, when I go to attack Solitude the soldiers that are supposed to be there never appear.
Among other problems... glitchiest game I've ever played by a mile.
PPS: Thanks to everyone for all of the comments and suggestions on this. It is very much appreciated.