At some point I was able to get this working with the steam version of wine and the Proton pfx, just not launched through the UI. I was able to install the missing dependencies in the Proton pfx and launch the game using the WINEPREFIX and the proton/dist/bin/wine. Something like:

cd ~/.local/Steam/SteamApps
WINEPREFIX= $PWD/compatdata/225080 winetricks corefonts dotnet40 tahoma  
WINEPREFIX= $PWD/compatdata/225080 \ 
"$PWD/common/Proton 3.7/dist/bin/wine" \ 
"$PWD/common/Brothers - A Tale of Two Sons/Binaries/Win32/BrothersLauncher.exe"

dotnet40/wine-mono points to #18 as @kisak-valve mentioned.
The corefonts issue would be solved by #571. It could also solve the tahoma issue.

I couldn't run BrothersLauncher.exe at all, tried it in several ways. The game installs and runs fine by setting OS in winecfg to Windows XP to cause .NET Framework install meanwhile first game setup. After that, I tried to install several .NET Framework versions to run BrothersLauncher.exe but it always comes with a different error. First it shows up a .NET Framework message box stating the version that's installed by default on game installation isn't the correct version to run the program, after installing dotnet40, same error, and after installing dotnet45, a new message box shows up stating .NET Framework is not enabled. Note that I had to put back mscoree.dlls after installing these frameworks by hand, because otherwise they're reported to be missing (they're removed on installation).

I wish to lower resolution, but since the launcher isn't working, no deal...

• GPU: Intel HD Graphics 630 (i7-7700K)
• Driver/LLVM version: mesa 18.2.3
• Kernel version: 4.18.16
• Proton version: 3.16-4

Game gets stuck on exit after playing it up to a checkpoint.

Got it running by simply installing dotnet40 twice through winetricks, like in Killer Is Dead and DmC.

https://github.com/ValveSoftware/Proton/issues/820#issuecomment-449672461

For me, this game works now out of the box with 4.2-8.
The "Brothers Launcher" is still not working and my 2560x1440 display shows black borders. Not sure if the game itself is limited to ~1080p or if this is an actual video issue.

Whitelist Request

• Name of the game to be whitelisted: Brothers: A Tale of Two Sons
• Steam AppID of the game: 225080

System Information

• GPU: AMD Radeon RX 5600 XT
• Driver/LLVM version: Mesa 20.1.6 / LLVM 10.0.0
• Distro version: Fedora 32 (Workstation Edition)
• Link to full system information report as Gist: https://gist.github.com/joshas/e5e75512e1eba926efa59fc8dd101f98
• Proton version: 5.0-9

I confirm:

• [x] that pressing the Play button in the Steam client is sufficient.
• [ ] that runtime config options are necessary to run the game.
• [ ] that no workarounds other than PROTON_* env variables are necessary.

Issues

• [x] I haven't experienced any issues.
• [x] There are no issues left open for this game.
• [ ] Although I consider the gaming experience equal to Windows there are remaining issues: