Hello All,
I'm dealing today with the same issue but my investigation shows so far that for me it is only related to PAL MD games

I opened a separate threat here with some more research : https://retropie.org.uk/forum/topic/34696/megadrive-50hz-games-with-genesis

The problem that I have if I use 1980 x 1020 @ 50Hz is that the monitor for whatever reason has black borders all around and I experience this on PI4B

How many raspberries on boot at the top left? If only one then you have a RPI1 not a 2.

@77claws Have you tried configuring the sound output from the Audio menu in RetroPie ? Choose the Headphones jack as the default sound output and it should route all audio over the 3.5mm jack.

I have the image for RetroPie 4.3. I was thinking about doing 4.2 instead. Should I, or is there something I'm missing?

@H3X1C https://retropie.org.uk/docs/Overclocking/

@sinfolmatt Please use the official installation instructions

https://github.com/retropie/retropie-setup/wiki/First-Installation

Note the part where it refers to downloading the correct image / number of raspberries shown on boot.